LKB1/AMPK Pathway and Drug Response in Cancer: A Therapeutic Perspective
Identifieur interne : 000A91 ( Pmc/Corpus ); précédent : 000A90; suivant : 000A92LKB1/AMPK Pathway and Drug Response in Cancer: A Therapeutic Perspective
Auteurs : Francesco Ciccarese ; Elisabetta Zulato ; Stefano IndraccoloSource :
- Oxidative Medicine and Cellular Longevity [ 1942-0900 ] ; 2019.
Abstract
Inactivating mutations of the tumor suppressor gene Liver Kinase B1 (
Url:
DOI: 10.1155/2019/8730816
PubMed: 31781355
PubMed Central: 6874879
Links to Exploration step
PMC:6874879Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">LKB1/AMPK Pathway and Drug Response in Cancer: A Therapeutic Perspective</title><author><name sortKey="Ciccarese, Francesco" sort="Ciccarese, Francesco" uniqKey="Ciccarese F" first="Francesco" last="Ciccarese">Francesco Ciccarese</name><affiliation><nlm:aff id="I1">Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy</nlm:aff></affiliation></author><author><name sortKey="Zulato, Elisabetta" sort="Zulato, Elisabetta" uniqKey="Zulato E" first="Elisabetta" last="Zulato">Elisabetta Zulato</name><affiliation><nlm:aff id="I1">Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy</nlm:aff></affiliation></author><author><name sortKey="Indraccolo, Stefano" sort="Indraccolo, Stefano" uniqKey="Indraccolo S" first="Stefano" last="Indraccolo">Stefano Indraccolo</name><affiliation><nlm:aff id="I1">Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31781355</idno><idno type="pmc">6874879</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874879</idno><idno type="RBID">PMC:6874879</idno><idno type="doi">10.1155/2019/8730816</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000A91</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000A91</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">LKB1/AMPK Pathway and Drug Response in Cancer: A Therapeutic Perspective</title><author><name sortKey="Ciccarese, Francesco" sort="Ciccarese, Francesco" uniqKey="Ciccarese F" first="Francesco" last="Ciccarese">Francesco Ciccarese</name><affiliation><nlm:aff id="I1">Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy</nlm:aff></affiliation></author><author><name sortKey="Zulato, Elisabetta" sort="Zulato, Elisabetta" uniqKey="Zulato E" first="Elisabetta" last="Zulato">Elisabetta Zulato</name><affiliation><nlm:aff id="I1">Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy</nlm:aff></affiliation></author><author><name sortKey="Indraccolo, Stefano" sort="Indraccolo, Stefano" uniqKey="Indraccolo S" first="Stefano" last="Indraccolo">Stefano Indraccolo</name><affiliation><nlm:aff id="I1">Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy</nlm:aff></affiliation></author></analytic><series><title level="j">Oxidative Medicine and Cellular Longevity</title><idno type="ISSN">1942-0900</idno><idno type="eISSN">1942-0994</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Inactivating mutations of the tumor suppressor gene Liver Kinase B1 (<italic>LKB1</italic>) are frequently detected in non-small-cell lung cancer (NSCLC) and cervical carcinoma. Moreover, LKB1 expression is epigenetically regulated in several tumor types. LKB1 has an established function in the control of cell metabolism and oxidative stress. Clinical and preclinical studies support a role of LKB1 as a central modifier of cellular response to different stress-inducing drugs, suggesting LKB1 pathway as a highly promising therapeutic target. Loss of LKB1-AMPK signaling confers sensitivity to energy depletion and to redox homeostasis impairment and has been associated with an improved outcome in advanced NSCLC patients treated with chemotherapy. In this review, we provide an overview of the interplay between LKB1 and its downstream targets in cancer and focus on potential therapeutic strategies whose outcome could depend from LKB1.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Jenne, D E" uniqKey="Jenne D">D. E. Jenne</name></author><author><name sortKey="Reomann, H" uniqKey="Reomann H">H. Reomann</name></author><author><name sortKey="Nezu, J I" uniqKey="Nezu J">J. I. Nezu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mehenni, H" uniqKey="Mehenni H">H. Mehenni</name></author><author><name sortKey="Gehrig, C" uniqKey="Gehrig C">C. Gehrig</name></author><author><name sortKey="Nezu, J I" uniqKey="Nezu J">J. I. Nezu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sanchez Cespedes, M" uniqKey="Sanchez Cespedes M">M. Sanchez-Cespedes</name></author><author><name sortKey="Parrella, P" uniqKey="Parrella P">P. Parrella</name></author><author><name sortKey="Esteller, M" uniqKey="Esteller M">M. Esteller</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Guldberg, P" uniqKey="Guldberg P">P. Guldberg</name></author><author><name sortKey="Straten, P" uniqKey="Straten P">P. . Straten</name></author><author><name sortKey="Ahrenkiel, V" uniqKey="Ahrenkiel V">V. Ahrenkiel</name></author><author><name sortKey="Seremet, T" uniqKey="Seremet T">T. Seremet</name></author><author><name sortKey="Kirkin, A F" uniqKey="Kirkin A">A. F. Kirkin</name></author><author><name sortKey="Zeuthen, J" uniqKey="Zeuthen J">J. Zeuthen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wingo, S N" uniqKey="Wingo S">S. N. Wingo</name></author><author><name sortKey="Gallardo, T D" uniqKey="Gallardo T">T. D. Gallardo</name></author><author><name sortKey="Akbay, E A" uniqKey="Akbay E">E. A. Akbay</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Shaw, R J" uniqKey="Shaw R">R. J. Shaw</name></author><author><name sortKey="Kosmatka, M" uniqKey="Kosmatka M">M. Kosmatka</name></author><author><name sortKey="Bardeesy, N" uniqKey="Bardeesy N">N. Bardeesy</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hardie, D G" uniqKey="Hardie D">D. G. Hardie</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ji, H" uniqKey="Ji H">H. Ji</name></author><author><name sortKey="Ramsey, M R" uniqKey="Ramsey M">M. R. Ramsey</name></author><author><name sortKey="Hayes, D N" uniqKey="Hayes D">D. N. Hayes</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Li, J" uniqKey="Li J">J. Li</name></author><author><name sortKey="Liu, J" uniqKey="Liu J">J. Liu</name></author><author><name sortKey="Li, P" uniqKey="Li P">P. Li</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Souroullas, G P" uniqKey="Souroullas G">G. P. Souroullas</name></author><author><name sortKey="Fedoriw, Y" uniqKey="Fedoriw Y">Y. Fedoriw</name></author><author><name sortKey="Staudt, L M" uniqKey="Staudt L">L. M. Staudt</name></author><author><name sortKey="Sharpless, N E" uniqKey="Sharpless N">N. E. Sharpless</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Liang, J" uniqKey="Liang J">J. Liang</name></author><author><name sortKey="Mills, G B" uniqKey="Mills G">G. B. Mills</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hearle, N" uniqKey="Hearle N">N. Hearle</name></author><author><name sortKey="Schumacher, V" uniqKey="Schumacher V">V. Schumacher</name></author><author><name sortKey="Menko, F H" uniqKey="Menko F">F. H. Menko</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sanchez Cespedes, M" uniqKey="Sanchez Cespedes M">M. Sanchez-Cespedes</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="He, T Y" uniqKey="He T">T. Y. He</name></author><author><name sortKey="Tsai, L H" uniqKey="Tsai L">L. H. Tsai</name></author><author><name sortKey="Huang, C C" uniqKey="Huang C">C. C. Huang</name></author><author><name sortKey="Chou, M C" uniqKey="Chou M">M. C. Chou</name></author><author><name sortKey="Lee, H" uniqKey="Lee H">H. Lee</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gill, R K" uniqKey="Gill R">R. K. Gill</name></author><author><name sortKey="Yang, S H" uniqKey="Yang S">S. H. Yang</name></author><author><name sortKey="Meerzaman, D" uniqKey="Meerzaman D">D. Meerzaman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Caiola, E" uniqKey="Caiola E">E. Caiola</name></author><author><name sortKey="Falcetta, F" uniqKey="Falcetta F">F. Falcetta</name></author><author><name sortKey="Giordano, S" uniqKey="Giordano S">S. Giordano</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Barta, J A" uniqKey="Barta J">J. A. Barta</name></author><author><name sortKey="Mcmahon, S B" uniqKey="Mcmahon S">S. B. McMahon</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Koivunen, J P" uniqKey="Koivunen J">J. P. Koivunen</name></author><author><name sortKey="Kim, J" uniqKey="Kim J">J. Kim</name></author><author><name sortKey="Lee, J" uniqKey="Lee J">J. Lee</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, Y S" uniqKey="Wang Y">Y. S. Wang</name></author><author><name sortKey="Chen, J" uniqKey="Chen J">J. Chen</name></author><author><name sortKey="Cui, F" uniqKey="Cui F">F. Cui</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jamal Hanjani, M" uniqKey="Jamal Hanjani M">M. Jamal-Hanjani</name></author><author><name sortKey="Wilson, G A" uniqKey="Wilson G">G. A. Wilson</name></author><author><name sortKey="Mcgranahan, N" uniqKey="Mcgranahan N">N. McGranahan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hawley, S A" uniqKey="Hawley S">S. A. Hawley</name></author><author><name sortKey="Boudeau, J" uniqKey="Boudeau J">J. Boudeau</name></author><author><name sortKey="Reid, J L" uniqKey="Reid J">J. L. Reid</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Woods, A" uniqKey="Woods A">A. Woods</name></author><author><name sortKey="Johnstone, S R" uniqKey="Johnstone S">S. R. Johnstone</name></author><author><name sortKey="Dickerson, K" uniqKey="Dickerson K">K. Dickerson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hardie, D G" uniqKey="Hardie D">D. G. Hardie</name></author><author><name sortKey="Alessi, D R" uniqKey="Alessi D">D. R. Alessi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hardie, D G" uniqKey="Hardie D">D. G. Hardie</name></author><author><name sortKey="Ross, F A" uniqKey="Ross F">F. A. Ross</name></author><author><name sortKey="Hawley, S A" uniqKey="Hawley S">S. A. Hawley</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hawley, S A" uniqKey="Hawley S">S. A. Hawley</name></author><author><name sortKey="Pan, D A" uniqKey="Pan D">D. A. Pan</name></author><author><name sortKey="Mustard, K J" uniqKey="Mustard K">K. J. Mustard</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Woods, A" uniqKey="Woods A">A. Woods</name></author><author><name sortKey="Dickerson, K" uniqKey="Dickerson K">K. Dickerson</name></author><author><name sortKey="Heath, R" uniqKey="Heath R">R. Heath</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hurley, R L" uniqKey="Hurley R">R. L. Hurley</name></author><author><name sortKey="Anderson, K A" uniqKey="Anderson K">K. A. Anderson</name></author><author><name sortKey="Franzone, J M" uniqKey="Franzone J">J. M. Franzone</name></author><author><name sortKey="Kemp, B E" uniqKey="Kemp B">B. E. Kemp</name></author><author><name sortKey="Means, A R" uniqKey="Means A">A. R. Means</name></author><author><name sortKey="Witters, L A" uniqKey="Witters L">L. A. Witters</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Vara Ciruelos, D" uniqKey="Vara Ciruelos D">D. Vara-Ciruelos</name></author><author><name sortKey="Dandapani, M" uniqKey="Dandapani M">M. Dandapani</name></author><author><name sortKey="Gray, A" uniqKey="Gray A">A. Gray</name></author><author><name sortKey="Egbani, E O" uniqKey="Egbani E">E. O. Egbani</name></author><author><name sortKey="Evans, A M" uniqKey="Evans A">A. M. Evans</name></author><author><name sortKey="Hardie, D G" uniqKey="Hardie D">D. G. Hardie</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fu, X" uniqKey="Fu X">X. Fu</name></author><author><name sortKey="Wan, S" uniqKey="Wan S">S. Wan</name></author><author><name sortKey="Lyu, Y L" uniqKey="Lyu Y">Y. L. Lyu</name></author><author><name sortKey="Liu, L F" uniqKey="Liu L">L. F. Liu</name></author><author><name sortKey="Qi, H" uniqKey="Qi H">H. Qi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sanli, T" uniqKey="Sanli T">T. Sanli</name></author><author><name sortKey="Rashid, A" uniqKey="Rashid A">A. Rashid</name></author><author><name sortKey="Liu, C" uniqKey="Liu C">C. Liu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhang, C S" uniqKey="Zhang C">C. S. Zhang</name></author><author><name sortKey="Hawley, S A" uniqKey="Hawley S">S. A. Hawley</name></author><author><name sortKey="Zong, Y" uniqKey="Zong Y">Y. Zong</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Carling, D" uniqKey="Carling D">D. Carling</name></author><author><name sortKey="Zammit, V A" uniqKey="Zammit V">V. A. Zammit</name></author><author><name sortKey="Hardie, D G" uniqKey="Hardie D">D. G. Hardie</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sato, R" uniqKey="Sato R">R. Sato</name></author><author><name sortKey="Goldstein, J L" uniqKey="Goldstein J">J. L. Goldstein</name></author><author><name sortKey="Brown, M S" uniqKey="Brown M">M. S. Brown</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hardie, D G" uniqKey="Hardie D">D. G. Hardie</name></author><author><name sortKey="Pan, D A" uniqKey="Pan D">D. A. Pan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jeon, S M" uniqKey="Jeon S">S. M. Jeon</name></author><author><name sortKey="Chandel, N S" uniqKey="Chandel N">N. S. Chandel</name></author><author><name sortKey="Hay, N" uniqKey="Hay N">N. Hay</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Shaw, R J" uniqKey="Shaw R">R. J. Shaw</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Liang, J" uniqKey="Liang J">J. Liang</name></author><author><name sortKey="Shao, S H" uniqKey="Shao S">S. H. Shao</name></author><author><name sortKey="Xu, Z X" uniqKey="Xu Z">Z. X. Xu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mihaylova, M M" uniqKey="Mihaylova M">M. M. Mihaylova</name></author><author><name sortKey="Shaw, R J" uniqKey="Shaw R">R. J. Shaw</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Faubert, B" uniqKey="Faubert B">B. Faubert</name></author><author><name sortKey="Boily, G" uniqKey="Boily G">G. Boily</name></author><author><name sortKey="Izreig, S" uniqKey="Izreig S">S. Izreig</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Herzig, S" uniqKey="Herzig S">S. Herzig</name></author><author><name sortKey="Shaw, R J" uniqKey="Shaw R">R. J. Shaw</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kim, J" uniqKey="Kim J">J. Kim</name></author><author><name sortKey="Kundu, M" uniqKey="Kundu M">M. Kundu</name></author><author><name sortKey="Viollet, B" uniqKey="Viollet B">B. Viollet</name></author><author><name sortKey="Guan, K L" uniqKey="Guan K">K. L. Guan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kim, J" uniqKey="Kim J">J. Kim</name></author><author><name sortKey="Yang, G" uniqKey="Yang G">G. Yang</name></author><author><name sortKey="Kim, Y" uniqKey="Kim Y">Y. Kim</name></author><author><name sortKey="Ha, J" uniqKey="Ha J">J. Ha</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gurumurthy, S" uniqKey="Gurumurthy S">S. Gurumurthy</name></author><author><name sortKey="Xie, S Z" uniqKey="Xie S">S. Z. Xie</name></author><author><name sortKey="Alagesan, B" uniqKey="Alagesan B">B. Alagesan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gan, B" uniqKey="Gan B">B. Gan</name></author><author><name sortKey="Hu, J" uniqKey="Hu J">J. Hu</name></author><author><name sortKey="Jiang, S" uniqKey="Jiang S">S. Jiang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nakada, D" uniqKey="Nakada D">D. Nakada</name></author><author><name sortKey="Saunders, T L" uniqKey="Saunders T">T. L. Saunders</name></author><author><name sortKey="Morrison, S J" uniqKey="Morrison S">S. J. Morrison</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Alessi, D R" uniqKey="Alessi D">D. R. Alessi</name></author><author><name sortKey="Sakamoto, K" uniqKey="Sakamoto K">K. Sakamoto</name></author><author><name sortKey="Bayascas, J R" uniqKey="Bayascas J">J. R. Bayascas</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jeon, S M" uniqKey="Jeon S">S. M. Jeon</name></author><author><name sortKey="Hay, N" uniqKey="Hay N">N. Hay</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lee, S W" uniqKey="Lee S">S. W. Lee</name></author><author><name sortKey="Li, C F" uniqKey="Li C">C. F. Li</name></author><author><name sortKey="Jin, G" uniqKey="Jin G">G. Jin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Trapp, E K" uniqKey="Trapp E">E. K. Trapp</name></author><author><name sortKey="Majunke, L" uniqKey="Majunke L">L. Majunke</name></author><author><name sortKey="Zill, B" uniqKey="Zill B">B. Zill</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Avtanski, D B" uniqKey="Avtanski D">D. B. Avtanski</name></author><author><name sortKey="Nagalingam, A" uniqKey="Nagalingam A">A. Nagalingam</name></author><author><name sortKey="Bonner, M Y" uniqKey="Bonner M">M. Y. Bonner</name></author><author><name sortKey="Arbiser, J L" uniqKey="Arbiser J">J. L. Arbiser</name></author><author><name sortKey="Saxena, N K" uniqKey="Saxena N">N. K. Saxena</name></author><author><name sortKey="Sharma, D" uniqKey="Sharma D">D. Sharma</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sharma, V K" uniqKey="Sharma V">V. K. Sharma</name></author><author><name sortKey="Raimondi, V" uniqKey="Raimondi V">V. Raimondi</name></author><author><name sortKey="Ruggero, K" uniqKey="Ruggero K">K. Ruggero</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rios, M" uniqKey="Rios M">M. Rios</name></author><author><name sortKey="Foretz, M" uniqKey="Foretz M">M. Foretz</name></author><author><name sortKey="Viollet, B" uniqKey="Viollet B">B. Viollet</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chhipa, R R" uniqKey="Chhipa R">R. R. Chhipa</name></author><author><name sortKey="Fan, Q" uniqKey="Fan Q">Q. Fan</name></author><author><name sortKey="Anderson, J" uniqKey="Anderson J">J. Anderson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Han, F" uniqKey="Han F">F. Han</name></author><author><name sortKey="Li, C F" uniqKey="Li C">C. F. Li</name></author><author><name sortKey="Cai, Z" uniqKey="Cai Z">Z. Cai</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fisher, K W" uniqKey="Fisher K">K. W. Fisher</name></author><author><name sortKey="Das, B" uniqKey="Das B">B. Das</name></author><author><name sortKey="Kim, H S" uniqKey="Kim H">H. S. Kim</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhang, P" uniqKey="Zhang P">P. Zhang</name></author><author><name sortKey="Lai, Z L" uniqKey="Lai Z">Z. L. Lai</name></author><author><name sortKey="Chen, H F" uniqKey="Chen H">H. F. Chen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pei, G" uniqKey="Pei G">G. Pei</name></author><author><name sortKey="Luo, M" uniqKey="Luo M">M. Luo</name></author><author><name sortKey="Ni, X" uniqKey="Ni X">X. Ni</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Weerasekara, V K" uniqKey="Weerasekara V">V. K. Weerasekara</name></author><author><name sortKey="Panek, D J" uniqKey="Panek D">D. J. Panek</name></author><author><name sortKey="Broadbent, D G" uniqKey="Broadbent D">D. G. Broadbent</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zou, Y" uniqKey="Zou Y">Y. Zou</name></author><author><name sortKey="Wang, Q" uniqKey="Wang Q">Q. Wang</name></author><author><name sortKey="Li, B" uniqKey="Li B">B. Li</name></author><author><name sortKey="Xie, B" uniqKey="Xie B">B. Xie</name></author><author><name sortKey="Wang, W" uniqKey="Wang W">W. Wang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Villanueva Paz, M" uniqKey="Villanueva Paz M">M. Villanueva-Paz</name></author><author><name sortKey="Cotan, D" uniqKey="Cotan D">D. Cotán</name></author><author><name sortKey="Garrido Maraver, J" uniqKey="Garrido Maraver J">J. Garrido-Maraver</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kroemer, G" uniqKey="Kroemer G">G. Kroemer</name></author><author><name sortKey="Levine, B" uniqKey="Levine B">B. Levine</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Shackelford, D B" uniqKey="Shackelford D">D. B. Shackelford</name></author><author><name sortKey="Vasquez, D S" uniqKey="Vasquez D">D. S. Vasquez</name></author><author><name sortKey="Corbeil, J" uniqKey="Corbeil J">J. Corbeil</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kim, D Y" uniqKey="Kim D">D. Y. Kim</name></author><author><name sortKey="Jung, S Y" uniqKey="Jung S">S. Y. Jung</name></author><author><name sortKey="Kim, Y J" uniqKey="Kim Y">Y. J. Kim</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhou, J" uniqKey="Zhou J">J. Zhou</name></author><author><name sortKey="Li, G" uniqKey="Li G">G. Li</name></author><author><name sortKey="Zheng, Y" uniqKey="Zheng Y">Y. Zheng</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Thomas, K J" uniqKey="Thomas K">K. J. Thomas</name></author><author><name sortKey="Jacobson, M R" uniqKey="Jacobson M">M. R. Jacobson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhang, H" uniqKey="Zhang H">H. Zhang</name></author><author><name sortKey="Liu, B" uniqKey="Liu B">B. Liu</name></author><author><name sortKey="Li, T" uniqKey="Li T">T. Li</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Silic Benussi, M" uniqKey="Silic Benussi M">M. Silic-Benussi</name></author><author><name sortKey="Scattolin, G" uniqKey="Scattolin G">G. Scattolin</name></author><author><name sortKey="Cavallari, I" uniqKey="Cavallari I">I. Cavallari</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Park, E J" uniqKey="Park E">E. J. Park</name></author><author><name sortKey="Kim, Y M" uniqKey="Kim Y">Y. M. Kim</name></author><author><name sortKey="Chang, K C" uniqKey="Chang K">K. C. Chang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pollak, M" uniqKey="Pollak M">M. Pollak</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Owen, M R" uniqKey="Owen M">M. R. Owen</name></author><author><name sortKey="Doran, E" uniqKey="Doran E">E. Doran</name></author><author><name sortKey="Halestrap, A P" uniqKey="Halestrap A">A. P. Halestrap</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Shackelford, D B" uniqKey="Shackelford D">D. B. Shackelford</name></author><author><name sortKey="Abt, E" uniqKey="Abt E">E. Abt</name></author><author><name sortKey="Gerken, L" uniqKey="Gerken L">L. Gerken</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Moro, M" uniqKey="Moro M">M. Moro</name></author><author><name sortKey="Caiola, E" uniqKey="Caiola E">E. Caiola</name></author><author><name sortKey="Ganzinelli, M" uniqKey="Ganzinelli M">M. Ganzinelli</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Curtarello, M" uniqKey="Curtarello M">M. Curtarello</name></author><author><name sortKey="Zulato, E" uniqKey="Zulato E">E. Zulato</name></author><author><name sortKey="Nardo, G" uniqKey="Nardo G">G. Nardo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bonanno, L" uniqKey="Bonanno L">L. Bonanno</name></author><author><name sortKey="Zulato, E" uniqKey="Zulato E">E. Zulato</name></author><author><name sortKey="Pavan, A" uniqKey="Pavan A">A. Pavan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Indraccolo, S" uniqKey="Indraccolo S">S. Indraccolo</name></author><author><name sortKey="Randon, G" uniqKey="Randon G">G. Randon</name></author><author><name sortKey="Zulato, E" uniqKey="Zulato E">E. Zulato</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Verbaanderd, C" uniqKey="Verbaanderd C">C. Verbaanderd</name></author><author><name sortKey="Maes, H" uniqKey="Maes H">H. Maes</name></author><author><name sortKey="Schaaf, M B" uniqKey="Schaaf M">M. B. Schaaf</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Molenaar, R J" uniqKey="Molenaar R">R. J. Molenaar</name></author><author><name sortKey="Coelen, R J S" uniqKey="Coelen R">R. J. S. Coelen</name></author><author><name sortKey="Khurshed, M" uniqKey="Khurshed M">M. Khurshed</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Shackelford, D B" uniqKey="Shackelford D">D. B. Shackelford</name></author><author><name sortKey="Shaw, R J" uniqKey="Shaw R">R. J. Shaw</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Contreras, C M" uniqKey="Contreras C">C. M. Contreras</name></author><author><name sortKey="Akbay, E A" uniqKey="Akbay E">E. A. Akbay</name></author><author><name sortKey="Gallardo, T D" uniqKey="Gallardo T">T. D. Gallardo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Liang, M C" uniqKey="Liang M">M. C. Liang</name></author><author><name sortKey="Ma, J" uniqKey="Ma J">J. Ma</name></author><author><name sortKey="Chen, L" uniqKey="Chen L">L. Chen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Li, F" uniqKey="Li F">F. Li</name></author><author><name sortKey="Han, X" uniqKey="Han X">X. Han</name></author><author><name sortKey="Li, F" uniqKey="Li F">F. Li</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Andrade Vieira, R" uniqKey="Andrade Vieira R">R. Andrade-Vieira</name></author><author><name sortKey="Goguen, D" uniqKey="Goguen D">D. Goguen</name></author><author><name sortKey="Bentley, H A" uniqKey="Bentley H">H. A. Bentley</name></author><author><name sortKey="Bowen, C V" uniqKey="Bowen C">C. V. Bowen</name></author><author><name sortKey="Marignani, P A" uniqKey="Marignani P">P. A. Marignani</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cheng, C" uniqKey="Cheng C">C. Cheng</name></author><author><name sortKey="Geng, F" uniqKey="Geng F">F. Geng</name></author><author><name sortKey="Cheng, X" uniqKey="Cheng X">X. Cheng</name></author><author><name sortKey="Guo, D" uniqKey="Guo D">D. Guo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Svensson, R U" uniqKey="Svensson R">R. U. Svensson</name></author><author><name sortKey="Parker, S J" uniqKey="Parker S">S. J. Parker</name></author><author><name sortKey="Eichner, L J" uniqKey="Eichner L">L. J. Eichner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sena, L A" uniqKey="Sena L">L. A. Sena</name></author><author><name sortKey="Chandel, N S" uniqKey="Chandel N">N. S. Chandel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hamanaka, R B" uniqKey="Hamanaka R">R. B. Hamanaka</name></author><author><name sortKey="Chandel, N S" uniqKey="Chandel N">N. S. Chandel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Maryanovich, M" uniqKey="Maryanovich M">M. Maryanovich</name></author><author><name sortKey="Gross, A" uniqKey="Gross A">A. Gross</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Trachootham, D" uniqKey="Trachootham D">D. Trachootham</name></author><author><name sortKey="Alexandre, J" uniqKey="Alexandre J">J. Alexandre</name></author><author><name sortKey="Huang, P" uniqKey="Huang P">P. Huang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Casares, C" uniqKey="Casares C">C. Casares</name></author><author><name sortKey="Ramirez Camacho, R" uniqKey="Ramirez Camacho R">R. Ramírez-Camacho</name></author><author><name sortKey="Trinidad, A" uniqKey="Trinidad A">A. Trinidad</name></author><author><name sortKey="Roldan, A" uniqKey="Roldan A">A. Roldán</name></author><author><name sortKey="Jorge, E" uniqKey="Jorge E">E. Jorge</name></author><author><name sortKey="Garcia Berrocal, J R" uniqKey="Garcia Berrocal J">J. R. García-Berrocal</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Alexandre, J" uniqKey="Alexandre J">J. Alexandre</name></author><author><name sortKey="Hu, Y" uniqKey="Hu Y">Y. Hu</name></author><author><name sortKey="Lu, W" uniqKey="Lu W">W. Lu</name></author><author><name sortKey="Pelicano, H" uniqKey="Pelicano H">H. Pelicano</name></author><author><name sortKey="Huang, P" uniqKey="Huang P">P. Huang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tsang, W P" uniqKey="Tsang W">W. P. Tsang</name></author><author><name sortKey="Chau, S P" uniqKey="Chau S">S. P. Chau</name></author><author><name sortKey="Kong, S K" uniqKey="Kong S">S. K. Kong</name></author><author><name sortKey="Fung, K P" uniqKey="Fung K">K. P. Fung</name></author><author><name sortKey="Kwok, T T" uniqKey="Kwok T">T. T. Kwok</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Iacobini, M" uniqKey="Iacobini M">M. Iacobini</name></author><author><name sortKey="Menichelli, A" uniqKey="Menichelli A">A. Menichelli</name></author><author><name sortKey="Palumbo, G" uniqKey="Palumbo G">G. Palumbo</name></author><author><name sortKey="Multari, G" uniqKey="Multari G">G. Multari</name></author><author><name sortKey="Werner, B" uniqKey="Werner B">B. Werner</name></author><author><name sortKey="Del Principe, D" uniqKey="Del Principe D">D. del Principe</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wu, B" uniqKey="Wu B">B. Wu</name></author><author><name sortKey="Tan, M" uniqKey="Tan M">M. Tan</name></author><author><name sortKey="Cai, W" uniqKey="Cai W">W. Cai</name></author><author><name sortKey="Wang, B" uniqKey="Wang B">B. Wang</name></author><author><name sortKey="He, P" uniqKey="He P">P. He</name></author><author><name sortKey="Zhang, X" uniqKey="Zhang X">X. Zhang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhang, R" uniqKey="Zhang R">R. Zhang</name></author><author><name sortKey="Humphreys, I" uniqKey="Humphreys I">I. Humphreys</name></author><author><name sortKey="Sahu, R P" uniqKey="Sahu R">R. P. Sahu</name></author><author><name sortKey="Shi, Y" uniqKey="Shi Y">Y. Shi</name></author><author><name sortKey="Srivastava, S K" uniqKey="Srivastava S">S. K. Srivastava</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, X" uniqKey="Wang X">X. Wang</name></author><author><name sortKey="Lu, X" uniqKey="Lu X">X. Lu</name></author><author><name sortKey="Zhu, R" uniqKey="Zhu R">R. Zhu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gandhy, S U" uniqKey="Gandhy S">S. U. Gandhy</name></author><author><name sortKey="Kim, K" uniqKey="Kim K">K. Kim</name></author><author><name sortKey="Larsen, L" uniqKey="Larsen L">L. Larsen</name></author><author><name sortKey="Rosengren, R J" uniqKey="Rosengren R">R. J. Rosengren</name></author><author><name sortKey="Safe, S" uniqKey="Safe S">S. Safe</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rabinovitch, R C" uniqKey="Rabinovitch R">R. C. Rabinovitch</name></author><author><name sortKey="Samborska, B" uniqKey="Samborska B">B. Samborska</name></author><author><name sortKey="Faubert, B" uniqKey="Faubert B">B. Faubert</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wu, S B" uniqKey="Wu S">S. B. Wu</name></author><author><name sortKey="Wei, Y H" uniqKey="Wei Y">Y. H. Wei</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ciccarese, F" uniqKey="Ciccarese F">F. Ciccarese</name></author><author><name sortKey="Ciminale, V" uniqKey="Ciminale V">V. Ciminale</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yu, W" uniqKey="Yu W">W. Yu</name></author><author><name sortKey="Dittenhafer Reed, K E" uniqKey="Dittenhafer Reed K">K. E. Dittenhafer-Reed</name></author><author><name sortKey="Denu, J M" uniqKey="Denu J">J. M. Denu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Xu, H G" uniqKey="Xu H">H. G. Xu</name></author><author><name sortKey="Zhai, Y X" uniqKey="Zhai Y">Y. X. Zhai</name></author><author><name sortKey="Chen, J" uniqKey="Chen J">J. Chen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zulato, E" uniqKey="Zulato E">E. Zulato</name></author><author><name sortKey="Ciccarese, F" uniqKey="Ciccarese F">F. Ciccarese</name></author><author><name sortKey="Nardo, G" uniqKey="Nardo G">G. Nardo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zulato, E" uniqKey="Zulato E">E. Zulato</name></author><author><name sortKey="Ciccarese, F" uniqKey="Ciccarese F">F. Ciccarese</name></author><author><name sortKey="Agnusdei, V" uniqKey="Agnusdei V">V. Agnusdei</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bonanno, L" uniqKey="Bonanno L">L. Bonanno</name></author><author><name sortKey="De Paoli, A" uniqKey="De Paoli A">A. de Paoli</name></author><author><name sortKey="Zulato, E" uniqKey="Zulato E">E. Zulato</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Singh, A" uniqKey="Singh A">A. Singh</name></author><author><name sortKey="Misra, V" uniqKey="Misra V">V. Misra</name></author><author><name sortKey="Thimmulappa, R K" uniqKey="Thimmulappa R">R. K. Thimmulappa</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kaufman, J M" uniqKey="Kaufman J">J. M. Kaufman</name></author><author><name sortKey="Amann, J M" uniqKey="Amann J">J. M. Amann</name></author><author><name sortKey="Park, K" uniqKey="Park K">K. Park</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kitamura, H" uniqKey="Kitamura H">H. Kitamura</name></author><author><name sortKey="Motohashi, H" uniqKey="Motohashi H">H. Motohashi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lee, S" uniqKey="Lee S">S. Lee</name></author><author><name sortKey="Lee, J S" uniqKey="Lee J">J. S. Lee</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ewald, J A" uniqKey="Ewald J">J. A. Ewald</name></author><author><name sortKey="Desotelle, J A" uniqKey="Desotelle J">J. A. Desotelle</name></author><author><name sortKey="Wilding, G" uniqKey="Wilding G">G. Wilding</name></author><author><name sortKey="Jarrard, D F" uniqKey="Jarrard D">D. F. Jarrard</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Han, X" uniqKey="Han X">X. Han</name></author><author><name sortKey="Tai, H" uniqKey="Tai H">H. Tai</name></author><author><name sortKey="Wang, X" uniqKey="Wang X">X. Wang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jung, Y R" uniqKey="Jung Y">Y. R. Jung</name></author><author><name sortKey="Kim, E J" uniqKey="Kim E">E. J. Kim</name></author><author><name sortKey="Choi, H J" uniqKey="Choi H">H. J. Choi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Castoldi, F" uniqKey="Castoldi F">F. Castoldi</name></author><author><name sortKey="Pietrocola, F" uniqKey="Pietrocola F">F. Pietrocola</name></author><author><name sortKey="Maiuri, M C" uniqKey="Maiuri M">M. C. Maiuri</name></author><author><name sortKey="Kroemer, G" uniqKey="Kroemer G">G. Kroemer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yi, G" uniqKey="Yi G">G. Yi</name></author><author><name sortKey="He, Z" uniqKey="He Z">Z. He</name></author><author><name sortKey="Zhou, X" uniqKey="Zhou X">X. Zhou</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Liao, E C" uniqKey="Liao E">E. C. Liao</name></author><author><name sortKey="Hsu, Y T" uniqKey="Hsu Y">Y. T. Hsu</name></author><author><name sortKey="Chuah, Q Y" uniqKey="Chuah Q">Q. Y. Chuah</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, Y" uniqKey="Wang Y">Y. Wang</name></author><author><name sortKey="Li, N" uniqKey="Li N">N. Li</name></author><author><name sortKey="Jiang, W" uniqKey="Jiang W">W. Jiang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jakhar, R" uniqKey="Jakhar R">R. Jakhar</name></author><author><name sortKey="Luijten, M N H" uniqKey="Luijten M">M. N. H. Luijten</name></author><author><name sortKey="Wong, A X F" uniqKey="Wong A">A. X. F. Wong</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Short, S" uniqKey="Short S">S. Short</name></author><author><name sortKey="Fielder, E" uniqKey="Fielder E">E. Fielder</name></author><author><name sortKey="Miwa, S" uniqKey="Miwa S">S. Miwa</name></author><author><name sortKey="Von Zglinicki, T" uniqKey="Von Zglinicki T">T. von Zglinicki</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kim, H S" uniqKey="Kim H">H. S. Kim</name></author><author><name sortKey="Mendiratta, S" uniqKey="Mendiratta S">S. Mendiratta</name></author><author><name sortKey="Kim, J" uniqKey="Kim J">J. Kim</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, Y" uniqKey="Wang Y">Y. Wang</name></author><author><name sortKey="Peng, R Q" uniqKey="Peng R">R. Q. Peng</name></author><author><name sortKey="Li, D D" uniqKey="Li D">D. D. Li</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Liu, L" uniqKey="Liu L">L. Liu</name></author><author><name sortKey="Han, C" uniqKey="Han C">C. Han</name></author><author><name sortKey="Yu, H" uniqKey="Yu H">H. Yu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Liu, F" uniqKey="Liu F">F. Liu</name></author><author><name sortKey="Shang, Y" uniqKey="Shang Y">Y. Shang</name></author><author><name sortKey="Chen, S Z" uniqKey="Chen S">S. Z. Chen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zou, Y" uniqKey="Zou Y">Y. Zou</name></author><author><name sortKey="Ling, Y H" uniqKey="Ling Y">Y. H. Ling</name></author><author><name sortKey="Sironi, J" uniqKey="Sironi J">J. Sironi</name></author><author><name sortKey="Schwartz, E L" uniqKey="Schwartz E">E. L. Schwartz</name></author><author><name sortKey="Perez Soler, R" uniqKey="Perez Soler R">R. Perez-Soler</name></author><author><name sortKey="Piperdi, B" uniqKey="Piperdi B">B. Piperdi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Liu, Y" uniqKey="Liu Y">Y. Liu</name></author><author><name sortKey="Marks, K" uniqKey="Marks K">K. Marks</name></author><author><name sortKey="Cowley, G S" uniqKey="Cowley G">G. S. Cowley</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Inge, L J" uniqKey="Inge L">L. J. Inge</name></author><author><name sortKey="Friel, J M" uniqKey="Friel J">J. M. Friel</name></author><author><name sortKey="Richer, A L" uniqKey="Richer A">A. L. Richer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cron, K R" uniqKey="Cron K">K. R. Cron</name></author><author><name sortKey="Zhu, K" uniqKey="Zhu K">K. Zhu</name></author><author><name sortKey="Kushwaha, D S" uniqKey="Kushwaha D">D. S. Kushwaha</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Garnett, M J" uniqKey="Garnett M">M. J. Garnett</name></author><author><name sortKey="Edelman, E J" uniqKey="Edelman E">E. J. Edelman</name></author><author><name sortKey="Heidorn, S J" uniqKey="Heidorn S">S. J. Heidorn</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kaufman, J M" uniqKey="Kaufman J">J. M. Kaufman</name></author><author><name sortKey="Yamada, T" uniqKey="Yamada T">T. Yamada</name></author><author><name sortKey="Park, K" uniqKey="Park K">K. Park</name></author><author><name sortKey="Timmers, C D" uniqKey="Timmers C">C. D. Timmers</name></author><author><name sortKey="Amann, J M" uniqKey="Amann J">J. M. Amann</name></author><author><name sortKey="Carbone, D P" uniqKey="Carbone D">D. P. Carbone</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Skoulidis, F" uniqKey="Skoulidis F">F. Skoulidis</name></author><author><name sortKey="Byers, L A" uniqKey="Byers L">L. A. Byers</name></author><author><name sortKey="Diao, L" uniqKey="Diao L">L. Diao</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Boudeau, J" uniqKey="Boudeau J">J. Boudeau</name></author><author><name sortKey="Deak, M" uniqKey="Deak M">M. Deak</name></author><author><name sortKey="Lawlor, M A" uniqKey="Lawlor M">M. A. Lawlor</name></author><author><name sortKey="Morrice, N A" uniqKey="Morrice N">N. A. Morrice</name></author><author><name sortKey="Alessi, D R" uniqKey="Alessi D">D. R. Alessi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Feng, F Y" uniqKey="Feng F">F. Y. Feng</name></author><author><name sortKey="De Bono, J S" uniqKey="De Bono J">J. S. de Bono</name></author><author><name sortKey="Rubin, M A" uniqKey="Rubin M">M. A. Rubin</name></author><author><name sortKey="Knudsen, K E" uniqKey="Knudsen K">K. E. Knudsen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Inge, L J" uniqKey="Inge L">L. J. Inge</name></author><author><name sortKey="Coon, K D" uniqKey="Coon K">K. D. Coon</name></author><author><name sortKey="Smith, M A" uniqKey="Smith M">M. A. Smith</name></author><author><name sortKey="Bremner, R M" uniqKey="Bremner R">R. M. Bremner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kim, D W" uniqKey="Kim D">D. W. Kim</name></author><author><name sortKey="Chung, H K" uniqKey="Chung H">H. K. Chung</name></author><author><name sortKey="Park, K C" uniqKey="Park K">K. C. Park</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Green, A S" uniqKey="Green A">A. S. Green</name></author><author><name sortKey="Chapuis, N" uniqKey="Chapuis N">N. Chapuis</name></author><author><name sortKey="Trovati Maciel, T" uniqKey="Trovati Maciel T">T. Trovati Maciel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ronan, B" uniqKey="Ronan B">B. Ronan</name></author><author><name sortKey="Flamand, O" uniqKey="Flamand O">O. Flamand</name></author><author><name sortKey="Vescovi, L" uniqKey="Vescovi L">L. Vescovi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bin Umer, M A" uniqKey="Bin Umer M">M. A. Bin-Umer</name></author><author><name sortKey="Mclaughlin, J E" uniqKey="Mclaughlin J">J. E. McLaughlin</name></author><author><name sortKey="Butterly, M S" uniqKey="Butterly M">M. S. Butterly</name></author><author><name sortKey="Mccormick, S" uniqKey="Mccormick S">S. McCormick</name></author><author><name sortKey="Tumer, N E" uniqKey="Tumer N">N. E. Tumer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Joo, M S" uniqKey="Joo M">M. S. Joo</name></author><author><name sortKey="Kim, W D" uniqKey="Kim W">W. D. Kim</name></author><author><name sortKey="Lee, K Y" uniqKey="Lee K">K. Y. Lee</name></author><author><name sortKey="Kim, J H" uniqKey="Kim J">J. H. Kim</name></author><author><name sortKey="Koo, J H" uniqKey="Koo J">J. H. Koo</name></author><author><name sortKey="Kim, S G" uniqKey="Kim S">S. G. Kim</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kapuy, O" uniqKey="Kapuy O">O. Kapuy</name></author><author><name sortKey="Papp, D" uniqKey="Papp D">D. Papp</name></author><author><name sortKey="Vellai, T" uniqKey="Vellai T">T. Vellai</name></author><author><name sortKey="Banhegyi, G" uniqKey="Banhegyi G">G. Banhegyi</name></author><author><name sortKey="Korcsmaros, T" uniqKey="Korcsmaros T">T. Korcsmaros</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Toyama, E Q" uniqKey="Toyama E">E. Q. Toyama</name></author><author><name sortKey="Herzig, S" uniqKey="Herzig S">S. Herzig</name></author><author><name sortKey="Courchet, J" uniqKey="Courchet J">J. Courchet</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fernandez Marcos, P J" uniqKey="Fernandez Marcos P">P. J. Fernandez-Marcos</name></author><author><name sortKey="Auwerx, J" uniqKey="Auwerx J">J. Auwerx</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kang, S W S" uniqKey="Kang S">S. W. S. Kang</name></author><author><name sortKey="Haydar, G" uniqKey="Haydar G">G. Haydar</name></author><author><name sortKey="Taniane, C" uniqKey="Taniane C">C. Taniane</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="review-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Oxid Med Cell Longev</journal-id><journal-id journal-id-type="iso-abbrev">Oxid Med Cell Longev</journal-id><journal-id journal-id-type="publisher-id">OMCL</journal-id><journal-title-group><journal-title>Oxidative Medicine and Cellular Longevity</journal-title></journal-title-group><issn pub-type="ppub">1942-0900</issn><issn pub-type="epub">1942-0994</issn><publisher><publisher-name>Hindawi</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31781355</article-id><article-id pub-id-type="pmc">6874879</article-id><article-id pub-id-type="doi">10.1155/2019/8730816</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review Article</subject></subj-group></article-categories><title-group><article-title>LKB1/AMPK Pathway and Drug Response in Cancer: A Therapeutic Perspective</article-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-7237-6942</contrib-id><name><surname>Ciccarese</surname><given-names>Francesco</given-names></name><xref ref-type="aff" rid="I1"></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-2624-5060</contrib-id><name><surname>Zulato</surname><given-names>Elisabetta</given-names></name><xref ref-type="aff" rid="I1"></xref></contrib><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-4810-7136</contrib-id><name><surname>Indraccolo</surname><given-names>Stefano</given-names></name><email>stefano.indraccolo@unipd.it</email><xref ref-type="aff" rid="I1"></xref></contrib></contrib-group><aff id="I1">Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy</aff><author-notes><fn fn-type="other"><p>Academic Editor: Cinzia Domenicotti</p></fn></author-notes><pub-date pub-type="collection"><year>2019</year></pub-date><pub-date pub-type="epub"><day>31</day><month>10</month><year>2019</year></pub-date><volume>2019</volume><elocation-id>8730816</elocation-id><history><date date-type="received"><day>12</day><month>4</month><year>2019</year></date><date date-type="rev-recd"><day>10</day><month>9</month><year>2019</year></date><date date-type="accepted"><day>16</day><month>9</month><year>2019</year></date></history><permissions><copyright-statement>Copyright © 2019 Francesco Ciccarese et al.</copyright-statement><copyright-year>2019</copyright-year><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions><abstract><p>Inactivating mutations of the tumor suppressor gene Liver Kinase B1 (<italic>LKB1</italic>) are frequently detected in non-small-cell lung cancer (NSCLC) and cervical carcinoma. Moreover, LKB1 expression is epigenetically regulated in several tumor types. LKB1 has an established function in the control of cell metabolism and oxidative stress. Clinical and preclinical studies support a role of LKB1 as a central modifier of cellular response to different stress-inducing drugs, suggesting LKB1 pathway as a highly promising therapeutic target. Loss of LKB1-AMPK signaling confers sensitivity to energy depletion and to redox homeostasis impairment and has been associated with an improved outcome in advanced NSCLC patients treated with chemotherapy. In this review, we provide an overview of the interplay between LKB1 and its downstream targets in cancer and focus on potential therapeutic strategies whose outcome could depend from LKB1.</p></abstract><funding-group><award-group><funding-source>Associazione Italiana per la Ricerca sul Cancro</funding-source><award-id>IG18803</award-id></award-group></funding-group></article-meta></front><body><sec id="sec1"><title>1. Introduction</title><p>The Liver Kinase B1 (<italic>LKB1</italic>, also known as <italic>STK11</italic>) is a tumor suppressor gene encoding a ubiquitously expressed and evolutionarily conserved serine threonine kinase, originally associated with the inherited cancer disorder Peutz-Jeghers Syndrome [<xref rid="B1" ref-type="bibr">1</xref>, <xref rid="B2" ref-type="bibr">2</xref>]. Inactivating somatic mutations of <italic>LKB1</italic> are frequently reported in non-small-cell lung cancer (NSCLC) [<xref rid="B3" ref-type="bibr">3</xref>], malignant melanoma [<xref rid="B4" ref-type="bibr">4</xref>], and cervical carcinoma [<xref rid="B5" ref-type="bibr">5</xref>]. LKB1 positively regulates the AMP-activated protein kinase (AMPK) [<xref rid="B6" ref-type="bibr">6</xref>] and at least 12 additional AMPK-related downstream kinases, involved in the control of cell growth and metabolism and in the regulation of cellular response to energy stress and establishment of cell polarity [<xref rid="B7" ref-type="bibr">7</xref>]. Deregulation of LKB1 signaling has been implicated in oncogenesis across many cancer types [<xref rid="B8" ref-type="bibr">8</xref>–<xref rid="B10" ref-type="bibr">10</xref>], although the energy-sensing function of LKB1-AMPK may also confer a survival advantage under unfavourable conditions [<xref rid="B11" ref-type="bibr">11</xref>].</p><p>Several preclinical studies identified LKB1 signaling axis as a potential modifier of response of cancer cells to different drugs. Thus, understanding the different mechanisms that account for anti- or prooncogenic effect of LKB1 is essential to identify therapeutic strategies targeting this pathway.</p><p>In this review, we address the potential vulnerabilities of LKB1-deficient tumors and focus on recent scientific findings that support a role of this pathway in the modulation of drug response in cancer.</p></sec><sec id="sec2"><title>2. LKB1 Alterations in Human Cancers</title><p>Germline loss of LKB1 kinase activity accounts for the Peutz-Jeghers Syndrome, an autosomal dominant inherited disorder characterized by hamartomatous polyps in the gastrointestinal tract and mucocutaneous pigmentation [<xref rid="B2" ref-type="bibr">2</xref>]. Peutz-Jeghers Syndrome is associated with age-related increased risk of cancer development, principally involving the gastrointestinal tract but affecting also the breast, gynecologic tract, lung, and other sites [<xref rid="B12" ref-type="bibr">12</xref>], corroborating a <italic>bona fide</italic> tumor suppressor role for LKB1.</p><p>In the great majority of human cancers, somatic mutations of the <italic>LKB1</italic> gene are rare. However, <italic>LKB1</italic> is the most frequently mutated gene in cervical carcinoma (20% of cases [<xref rid="B5" ref-type="bibr">5</xref>]) and the third most mutated gene in NSCLC (30% of cases in the Caucasian population [<xref rid="B13" ref-type="bibr">13</xref>]). Frequent somatic <italic>LKB1</italic> loss in lung adenocarcinoma is puzzling, as lung cancer is uncommon in Peutz-Jeghers patients. In contrast, <italic>LKB1</italic> somatic mutations are rare in colorectal cancer [<xref rid="B14" ref-type="bibr">14</xref>], the most frequent neoplasia associated with inherited <italic>LKB1</italic> loss. Several factors could account for these differences. First, <italic>LKB1</italic> loss in NSCLC is frequently homozygous [<xref rid="B15" ref-type="bibr">15</xref>], indicating that probably monoallelic LKB1 in Peutz-Jeghers patients is sufficient to limit lung tumorigenesis. Second, <italic>LKB1</italic> mutations coexist with several other genetic alterations in sporadic cancers. <italic>TP53</italic> and <italic>KRAS</italic> are, respectively, the first and the second most mutated genes in lung adenocarcinoma. About 12% of NSCLC cases have <italic>LKB1</italic> and <italic>KRAS</italic> comutations [<xref rid="B16" ref-type="bibr">16</xref>]. Moreover, <italic>LKB1</italic> mutations cooccur with gain-of-function <italic>TP53</italic> mutations in 8.2% lung adenocarcinomas [<xref rid="B17" ref-type="bibr">17</xref>]. Third, <italic>LKB1</italic> mutations are associated with smoking history of NSCLC patients [<xref rid="B18" ref-type="bibr">18</xref>]. Fourth, by interacting with breast cancer susceptibility 1 (BRCA1), LKB1 is involved in the DNA damage response, promoting homologous recombination (<xref ref-type="fig" rid="fig1">Figure 1</xref>) and fostering genomic stability [<xref rid="B19" ref-type="bibr">19</xref>]. In light of these considerations, <italic>LKB</italic>1 loss could be induced by and, afterwards, facilitate the mutagenic properties of carcinogens contained in tobacco smoke, being selected to promote lung tumorigenesis, while other malignancies—such as colon cancer—have evolved different protumorigenic alterations.</p><p>An interesting feature of NSCLC is its intratumor heterogeneity. Remarkably, somatic <italic>LKB1</italic> loss is an intermediate event during lung carcinogenesis, which arises clonally in lung cells with preexisting mutations in initiating drivers, such as <italic>TP53</italic> and <italic>KRAS</italic> [<xref rid="B20" ref-type="bibr">20</xref>]. The subclonal nature of <italic>LKB1</italic> highlights how the complexity of cancer genetics might impact on tumor progression and resistance to therapy.</p><p>Considering all the genetic and epigenetic events that can affect the <italic>LKB1</italic> gene, the estimated real frequency of <italic>LKB1</italic> alterations in NSCLC is as high as 90% [<xref rid="B15" ref-type="bibr">15</xref>], hinting at its fundamental role in lung cancer biology. Moreover, it should be emphasized that the frequency of LKB1 loss in other cancer types could be underestimated, due to rarely investigated epigenetic alterations. A paradigmatic example is breast cancer, whose aggressiveness and metastasis are promoted by LKB1 loss [<xref rid="B9" ref-type="bibr">9</xref>], even if <italic>LKB1</italic> mutations are detected with low frequency. The combination of sequencing and analysis of protein expression might overcome intrinsic limitations of sequencing and provide a comprehensive evaluation of LKB1 status in tumors.</p></sec><sec id="sec3"><title>3. Role of LKB1-AMPK Pathway in Cell Metabolism</title><p>LKB1 was identified as the critical upstream kinase required for AMPK activation [<xref rid="B6" ref-type="bibr">6</xref>, <xref rid="B21" ref-type="bibr">21</xref>, <xref rid="B22" ref-type="bibr">22</xref>] (<xref ref-type="fig" rid="fig1">Figure 1</xref>), thus providing a direct link between a known tumor suppressor and regulation of metabolism [<xref rid="B23" ref-type="bibr">23</xref>]. AMPK has a central role in the regulation of energy metabolism in eukaryotes and coordinates glucose and lipid metabolism in response to alterations in nutrients and intracellular energy levels, contributing to maintain steady-state levels of intracellular ATP [<xref rid="B24" ref-type="bibr">24</xref>].</p><p>Upon changes in energy availability, causing perturbations in the ATP-to-ADP or ATP-to-AMP ratio, AMPK is activated by an allosteric mechanism and by LKB1 via phosphorylation [<xref rid="B7" ref-type="bibr">7</xref>]. AMPK is also activated by increases in intracellular Ca<sup>2+</sup> [<xref rid="B25" ref-type="bibr">25</xref>–<xref rid="B27" ref-type="bibr">27</xref>] and by DNA damage [<xref rid="B28" ref-type="bibr">28</xref>–<xref rid="B30" ref-type="bibr">30</xref>]. Moreover, a novel AMP-independent mechanism of AMPK activation under glucose starvation has recently been described by Zhang and colleagues who observed that, upon glucose starvation and the consequent decrease of fructose-1,6-bisphosphate (FBP) levels, aldolases promote the formation of a lysosomal complex containing v-ATPase, Ragulator, AXIN/LKB1, and AMPK [<xref rid="B31" ref-type="bibr">31</xref>], leading to LKB1-mediated AMPK activation before energy levels fall. This aldolase-dependent mechanism of AMPK activation could be at play under conditions where low glucose does not cause an increase of intracellular AMP-to-ATP or ADP-to-ATP ratios.</p><p>Once activated, AMPK redirects metabolism towards decreased anabolism and increased catabolism by phosphorylation of key proteins involved in several metabolic pathways [<xref rid="B24" ref-type="bibr">24</xref>], including lipid homeostasis, glycolysis, protein synthesis, and mitochondrial homeostasis.</p><p>AMPK was originally defined as the critical inhibitory upstream kinase for the metabolic enzymes acetyl-CoA carboxylase (ACC1 and ACC2) [<xref rid="B32" ref-type="bibr">32</xref>] (<xref ref-type="fig" rid="fig1">Figure 1</xref>) and HMG-CoA reductase [<xref rid="B33" ref-type="bibr">33</xref>], which serve as rate-limiting steps for fatty acid and sterol synthesis, respectively, in a wide variety of eukaryotes. Moreover, inactivation of ACC2 switches on fatty acid (FA) <italic>β</italic>-oxidation in mitochondria [<xref rid="B34" ref-type="bibr">34</xref>]. Through activation of FA oxidation and inhibition of FA synthesis, LKB1-AMPK pathway plays a pivotal role in the maintenance of intracellular NADPH levels, which is required to prevent oxidative stress and to promote cancer cell survival under energy stress conditions [<xref rid="B35" ref-type="bibr">35</xref>].</p><p>Moreover, when nutrient levels are low, AMPK acts as a metabolic checkpoint inhibitor of cell growth, by modulation of the master regulator of growth, the mammalian target of rapamycin (mTOR) pathway [<xref rid="B36" ref-type="bibr">36</xref>] (<xref ref-type="fig" rid="fig1">Figure 1</xref>). AMPK activation leads to inhibition of mTOR complex 1 (mTORC1), by activation of the negative mTORC1 regulator TSC2 and by inhibition of the mTORC1 subunit RAPTOR [<xref rid="B36" ref-type="bibr">36</xref>]. Importantly, activated mTORC1 is localized on the surface of lysosomes, where it is negatively regulated by AXIN through inhibition of the GEF (guanine nucleotide exchange factor) activity of Ragulator. Thus, AXIN/LKB1 complex inhibits mTORC1 through the glucose-sensing mechanism involving aldolase and FBP [<xref rid="B31" ref-type="bibr">31</xref>]. Moreover, AMPK activation caused G1 cell cycle arrest associated with activation of p53, followed by induction of the cell cycle inhibition protein p21 and by stabilization via phosphorylation of the cyclin-dependent kinase inhibitor p27<sup>kip1</sup> [<xref rid="B37" ref-type="bibr">37</xref>, <xref rid="B38" ref-type="bibr">38</xref>]. Through mTOR inhibition, AMPK downregulates hypoxia-inducible factor 1<italic>α</italic> (HIF-1<italic>α</italic>), thus counteracting the Warburg effect [<xref rid="B39" ref-type="bibr">39</xref>].</p><p>In addition to its central role in the regulation of cell growth, mTORC1 controls autophagy, a lysosome-dependent catabolic program that maintains cellular homeostasis. Upon nutrient starvation, mTORC1 is inactivated through the energy-sensing mechanism of AMPK activation. Moreover, mTORC1 is also inhibited by direct dissociation from lysosomes through the glucose-sensing mechanism [<xref rid="B31" ref-type="bibr">31</xref>]. This mTORC1 suppression relieves the inhibitory phosphorylation on Unc-51-Like Autophagy Activating Kinase 1 (ULK1), a kinase essential for autophagy induction [<xref rid="B40" ref-type="bibr">40</xref>, <xref rid="B41" ref-type="bibr">41</xref>]. AMPK has also an important role in the regulation of autophagy through direct phosphorylation of ULK1 and of a second autophagy-initiating regulator, the lipid kinase complex PI32KC3/VPS34 [<xref rid="B42" ref-type="bibr">42</xref>]. Interestingly, AMPK triggers acute destruction of dysfunctional mitochondria through ULK1-dependent stimulation of mitophagy (<xref ref-type="fig" rid="fig1">Figure 1</xref>), and it stimulates <italic>de novo</italic> mitochondrial biogenesis through peroxisome proliferator-activated receptor gamma coactivator 1 <italic>α</italic>- (PGC-1<italic>α</italic>-) dependent transcription [<xref rid="B38" ref-type="bibr">38</xref>]. Interestingly, genetic deletion of <italic>Lkb1</italic> in the haematopoietic stem cell resulted in mitochondrial dysfunction and deregulation of bioenergetic processes through AMPK-dependent and independent mechanisms [<xref rid="B43" ref-type="bibr">43</xref>–<xref rid="B45" ref-type="bibr">45</xref>]. The interplay between AMPK and mitochondria is further discussed in a distinct section.</p><p>Besides AMPK, other 12 kinases, collectively termed AMPK-related kinases, are LKB1 substrates. However, little is known about what stimuli direct LKB1 towards any of these AMPK-related kinases. These enzymes include two family members, SNARK/Nuak2 and SIK2, both activated under low energy conditions, although only AMPK is activated under low ATP levels [<xref rid="B36" ref-type="bibr">36</xref>]. Moreover, other members, such as isoforms of PAR1/MARK, as well as SAD/BRSK, unlike AMPK, are not activated by energy stress but have been implicated in controlling cell polarity [<xref rid="B46" ref-type="bibr">46</xref>].</p><sec id="sec3.1"><title>3.1. LKB1: An Unexpected Oncogenic Role for a Tumor Suppressor</title><p>Recently, the role of LKB1-AMPK to sense different types of stress has pointed at a conditional oncogenic role of this pathway. In fact, its ability to modulate cell metabolism in order to restore homeostasis may confer a survival advantage under selective pressure, by favoring adaptation to hostile conditions [<xref rid="B47" ref-type="bibr">47</xref>]. In this context, Lee and colleagues demonstrated that polyubiquitination of LKB1 by S-Phase Kinase-Associated Protein 2 (Skp2) ubiquitin ligase promotes its persistent activation, leading to cell survival and poor outcome in hepatocellular carcinoma patients [<xref rid="B48" ref-type="bibr">48</xref>]. A recent study showed that, although it negatively regulates the epithelial-to-mesenchymal transition (EMT)-inducing gene <italic>ZEB1</italic>, LKB1 expression is increased in spheroids obtained from breast cancer cell lines and its ablation induces anoikis, suggesting that LKB1 promotes survival of circulating tumor cells [<xref rid="B49" ref-type="bibr">49</xref>]. LKB1 activation can result in an oncogenic program based on the contextual oncogenic role of its targets. For instance, LKB1 upregulates the expression of miR-34a [<xref rid="B50" ref-type="bibr">50</xref>], which was found to promote survival in the context of adult T-cell leukemia/lymphoma (ATLL) [<xref rid="B51" ref-type="bibr">51</xref>].</p><p>Downstream of LKB1, also AMPK has been indicated as a contextual oncogene. In fact, AMPK activation promotes glioblastoma growth by inducing lipid internalization [<xref rid="B52" ref-type="bibr">52</xref>] and sustains bioenergetics of glioblastoma through HIF-1<italic>α</italic> signaling [<xref rid="B53" ref-type="bibr">53</xref>]. Moreover, AMPK activation results in increased AKT oncogenic signaling through Skp2 phosphorylation under stress [<xref rid="B54" ref-type="bibr">54</xref>] and promotes aberrant expression of PGC-1<italic>β</italic> and estrogen-related receptor <italic>α</italic> (ERR<italic>α</italic>) in colon cancer, supporting its survival [<xref rid="B55" ref-type="bibr">55</xref>]. Finally, AMPK activation promotes resistance of cancer cells to chemotherapy by induction of autophagy [<xref rid="B56" ref-type="bibr">56</xref>–<xref rid="B59" ref-type="bibr">59</xref>].</p><p>How can the contrasting role of LKB1 as a tumor suppressor or promoter of cancer survival be reconciled? It must be considered that this pathway has evolved to allow cell survival under energy stress. During the initial phases of tumorigenesis, stress is a critical event that alters cell physiology and induces genetic aberrations, genomic instability, and transformation. In this context, LKB1 and AMPK play a tumor suppressor role by dealing with metabolic stress. The maintenance of genomic integrity, activation of autophagy, which scavenges damaged organelles and proteins, and activation of TP53 [<xref rid="B14" ref-type="bibr">14</xref>] to eliminate aberrant cells blunt cancer initiation. However, stress is a double-edged sword in cancer, and if not solved, it would lead to tumor eradication. In this scenario, a functional LKB1-AMPK pathway is advantageous for growing cancer cells, as it promotes adaption to a hostile microenvironment and cell survival. The activation of catabolic pathways and increased recycling of cellular components through autophagy ensure maintenance of energy homeostasis [<xref rid="B60" ref-type="bibr">60</xref>]. Autophagy, which has both prosurvival and prodeath effects, is probably the main responsible for contextual tumor suppressor and oncogenic activities of LKB1-AMPK. It should be pointed out, however, that autophagic cell death is a concept that should be cautiously evaluated. Cell death occurs, likely, despite autophagy, rather than because of autophagy [<xref rid="B61" ref-type="bibr">61</xref>]. In fact, increased autophagy in dying cells could be a rescue mechanism that failed or a mechanism sustaining apoptosis through ATP production. Physiologic “tumor suppressor” autophagy, which degrades damaged organelles and suppresses tumor initiation, should be distinguished by aberrant “prosurvival” autophagy, which is coopted by cancer to sustain its growth. As degradation of cellular components that have been damaged by anticancer therapies is a widely adopted mechanism of resistance, activation of autophagy by LKB1-AMPK in advanced stage cancers could represent a rescue mechanism.</p></sec></sec><sec id="sec4"><title>4. Mitochondrial Dynamics Is Affected by LKB1-AMPK Pathway</title><p>As master regulators of metabolism, LKB1 and AMPK are tightly intertwined with mitochondrial function and dynamics (<xref ref-type="fig" rid="fig1">Figure 1</xref>). Mitochondria are essential dynamic organelles that continuously shift from fusion to fission and vice versa. Mitochondrial dynamics is in part regulated by the LKB1-AMPK pathway (<xref rid="tab1" ref-type="table">Table 1</xref>). Following stress, AMPK activates mitochondrial fusion to restore the function of damaged mitochondria. If the damage is too extensive, AMPK activates mitochondrial fission and mitophagy to separate and degrade damaged mitochondrial portions and promotes synthesis of new mitochondria, in order to preserve mitochondrial network function and maximize ATP production (<xref rid="tab1" ref-type="table">Table 1</xref>). In contrast, in LKB1 defective tumors, hypoxic stress elicits activation of HIF-1<italic>α</italic> [<xref rid="B62" ref-type="bibr">62</xref>], which reduces the expression of Mitofusin-1 (MFN1) and Optic Atrophy 1 (OPA1) and increases activity of Dynamin-Related Protein 1 (DRP1), thus unbalancing mitochondrial dynamics towards fission (<xref ref-type="fig" rid="fig2">Figure 2</xref>). In endothelial cells, this promotes migration, invasion, and tube formation, implying that hypoxia-induced mitochondrial fission activates angiogenesis [<xref rid="B63" ref-type="bibr">63</xref>].</p><p>Mitochondria fusion and fission are both involved in the response of cancer cells to therapies. Several studies observed that mitochondrial fission sensitizes cancer cells to chemotherapy. Inhibition of autophagy has been shown to enhance doxorubicin cytotoxicity in breast cancer cells through mitochondrial translocation of DRP1 and consequent mitochondrial fission [<xref rid="B64" ref-type="bibr">64</xref>]. Similarly, LKB1-deficient NSCLC cell line A549 resulted resistant to doxorubicin-induced apoptotic cell death due to dysfunctional DRP1 that impedes mitochondrial fission [<xref rid="B65" ref-type="bibr">65</xref>]. Notably, AMPK promotes the maintenance of mitochondrial membrane potential following stress [<xref rid="B66" ref-type="bibr">66</xref>], thus preventing the proteolytic cleavage of OPA1, which is involved in cell death induction [<xref rid="B67" ref-type="bibr">67</xref>].</p><p>In cancer cells, mitochondrial fission has also been described to trigger cell migration, leading to cell escape from stressful conditions, such as chemotherapy, metastasis, and chemoresistance. By decreasing reactive oxygen species (ROS) levels—as described later—AMPK inhibits the release of high mobility group box 1 (HMGB1), which is involved in mitochondrial fission [<xref rid="B68" ref-type="bibr">68</xref>], thus blunting these escape mechanisms.</p></sec><sec id="sec5"><title>5. Targeting the LKB1-AMPK Pathway</title><sec id="sec5.1"><title>5.1. Activation of LKB1-AMPK Pathway by Biguanides</title><p>The biguanide metformin attracted considerable attention as a potential anticancer drug once the connection between LKB1 and AMPK was discovered [<xref rid="B42" ref-type="bibr">42</xref>]. Metformin is one of the most widely used type 2 diabetes drug worldwide, and epidemiological studies revealed that diabetic patients taking metformin show a statistically significant reduced tumor incidence [<xref rid="B69" ref-type="bibr">69</xref>].</p><p>Metformin and the related drug phenformin have been shown to inhibit complex I of the mitochondria [<xref rid="B70" ref-type="bibr">70</xref>], resulting in increased intracellular AMP and ADP levels, which trigger LKB1-dependent phosphorylation of AMPK [<xref rid="B42" ref-type="bibr">42</xref>]. Diabetic patients taking biguanides might have a lower incidence of cancer because of the role of the LKB1-AMPK pathway as a checkpoint inhibitor of cell growth and suppression of mTORC1 and other growth pathways. In addition, antitumor effects of metformin might be linked to its ability to lower circulating blood glucose and insulin levels, which also contribute to cancer risk and incidence in some contexts [<xref rid="B69" ref-type="bibr">69</xref>].</p><p>Tumor cells lacking functional LKB1 are acutely sensitive to metabolic stress, resulting in rapid apoptosis, likely a consequence of their inability to sense energy stress and activate mechanisms to restore energy homeostasis [<xref rid="B6" ref-type="bibr">6</xref>]. Taking advantage of these observations, Shackelford and colleagues tested the therapeutic potential of phenformin in <italic>LKB1</italic>-deficient NSCLC experimental tumors. Phenformin as a single agent reduced tumor burden in <italic>KRAS</italic>/<italic>LKB1</italic> comutated murine NSCLC. In particular, LKB1 inactivation renders NSCLC cells unable to modulate anabolic processes in conditions of metabolic stress caused by phenformin. The constitutive activation of KRAS pathway forced cells to duplicate their DNA and other intracellular structures, thus accelerating energy depletion and damage to intracellular components and triggering apoptosis [<xref rid="B71" ref-type="bibr">71</xref>].</p><p>In a recent study, it has been speculated that the metabolic frailty of <italic>KRAS</italic>/<italic>LKB1</italic> comutated NSCLC cells could be exploited pharmacologically by the combination of metformin with compounds that increase intracellular stress by interfering with DNA replication and repair, such as platinum compounds [<xref rid="B72" ref-type="bibr">72</xref>]. Metformin has been demonstrated to induce apoptosis in <italic>KRAS</italic>/<italic>LKB1</italic> comutated experimental tumors. On the contrary, in <italic>KRAS</italic><sup>wt</sup>/<italic>LKB1</italic><sup>wt</sup> cells or in the <italic>KRAS<sup>mut</sup></italic>/<italic>LKB1</italic><sup>wt</sup> experimental tumors, metformin determined activation of the LKB1/AMPK signaling pathway, thus reducing cell proliferation and metabolic requirements and preventing metabolic crisis in cancer cells. Treatment with metformin was also associated with enhanced cisplatin-induced <italic>in vitro</italic> proapoptotic and <italic>in vivo</italic> antitumor effects specifically in <italic>KRAS</italic>/<italic>LKB1</italic> comutated tumors [<xref rid="B72" ref-type="bibr">72</xref>].</p><p>The opportunity to target dysregulated metabolic features in <italic>LKB1</italic> mutated tumors could represent a strategy to improve therapeutic efficacy of other compounds affecting cell metabolism. In this regard, stable upregulation of glycolysis in tumor cells has been observed following antiangiogenic treatment [<xref rid="B73" ref-type="bibr">73</xref>], and as a master regulator of tumor cell metabolism and tumor microenvironment, LKB1/AMPK has a role in tumor response to VEGF neutralization [<xref rid="B74" ref-type="bibr">74</xref>]. Thus, sequential or simultaneous combination of antiangiogenic drugs and metformin might represent a new treatment opportunity for LKB1-deficient tumors. Although clinical and preclinical data are fragmentary, a case of a terminally ill patient with advanced endometrial cancer, showing radiological response to simultaneous administration of metformin and bevacizumab, was described by our group [<xref rid="B75" ref-type="bibr">75</xref>]. Interestingly, the high expression of MCT4—a marker of enhanced glycolysis—and loss of LKB1 expression were detected in the patient's liver metastasis sample. These findings suggest that metformin could modulate bevacizumab activity in tumors lacking LKB1 expression and deserves further validation in preclinical studies and clinical trials.</p><p>As previously described, autophagy represents a cellular process directed to preserve cellular homeostasis. Complementary with aforementioned findings, the ability to sense and counteract different types of stresses of LKB1 proficient tumor cells might be targeted by the combination of AMPK activators, such as metformin, and autophagy inhibitors, such as chloroquine, which has been recently repurposed as an anticancer agent [<xref rid="B76" ref-type="bibr">76</xref>]. Speculatively, this combination, currently evaluated in clinical trials [<xref rid="B77" ref-type="bibr">77</xref>], should potentiate the tumor suppressor activity of LKB1-AMPK by inhibiting its oncogenic prosurvival activity.</p></sec><sec id="sec5.2"><title>5.2. Targeting the Downstream Effectors of LKB1 Pathway</title><sec id="sec5.2.1"><title>5.2.1. Inhibition of mTOR</title><p>Since LKB1 inactivation promotes mTORC1 signaling [<xref rid="B46" ref-type="bibr">46</xref>, <xref rid="B78" ref-type="bibr">78</xref>] (<xref ref-type="fig" rid="fig2">Figure 2</xref>), mTOR inhibitors have been extensively tested as a therapeutic approach to target <italic>LKB1</italic> mutated tumors. However, preclinical studies produced controversial results. LKB1 inactivation in endometrial cancers resulted in high responsiveness to mTOR inhibitors [<xref rid="B79" ref-type="bibr">79</xref>], and rapamycin monotherapy (mTORC1 inhibitor) decreased polyp burden and size in LKB1<sup>+/−</sup> mice with polyposis [<xref rid="B62" ref-type="bibr">62</xref>]. In contrast, <italic>LKB1</italic> gene inactivation in NSCLC cells did not increase sensitivity to mTORC1 inhibitors, through negative feedback activation of AKT [<xref rid="B80" ref-type="bibr">80</xref>]. The same mechanism of escape to rapamycin could be at play in <italic>Lkb1</italic>-inactivated lung adenocarcinoma mouse model [<xref rid="B81" ref-type="bibr">81</xref>]. On the other hand, simultaneous inhibition of mTOR and glycolysis was significantly effective at reducing tumor volume and burden in a mouse model of spontaneous breast cancer promoted by loss of LKB1 in an ErbB2 activated model [<xref rid="B82" ref-type="bibr">82</xref>]. Given the master regulatory role of mTOR signaling in cell growth, additional preclinical and clinical studies are required in order to establish the appropriate genetic and molecular setting that could influence response to inhibition of mTOR pathway in the context of LKB1 status.</p></sec><sec id="sec5.2.2"><title>5.2.2. Inhibition of ACC Activity</title><p><italic>De novo</italic> FA synthesis is essential to sustain rapid tumor growth, and reprogramming of lipid metabolism is a newly recognized hallmark of malignancy. Targeting altered lipid metabolic pathways has become a promising anticancer strategy [<xref rid="B83" ref-type="bibr">83</xref>]. Lipid-lowering drugs are being considered for clinical trials, showing their advantages in comparison with other anticancer drugs with high toxicity [<xref rid="B83" ref-type="bibr">83</xref>]. Since AMPK inhibits activity of ACC [<xref rid="B32" ref-type="bibr">32</xref>], the rate-limiting enzyme required for <italic>de novo</italic> FA synthesis, the latter might represent a potential metabolic target in tumors lacking LKB1. Inactivation of LKB1 in the adenocarcinoma mouse model determined accumulation of lipids and low levels of FA oxidation signature genes [<xref rid="B81" ref-type="bibr">81</xref>]. In preclinical models, ACC was required to maintain <italic>de novo</italic> FA synthesis needed for growth and viability of NSCLC cells, and its pharmacological inhibition results in robust inhibition of tumor growth [<xref rid="B84" ref-type="bibr">84</xref>]. Administration of ND-646—an allosteric inhibitor of the ACC enzymes ACC1 and ACC2 that prevents ACC subunit dimerization—as a single agent or in combination with the standard-of-care drug carboplatin markedly suppressed lung tumor growth in NSCLC xenograft from LKB1-deficient cells [<xref rid="B84" ref-type="bibr">84</xref>]. Effects of ACC inhibition on tumor growth fit its critical role in maintaining <italic>de novo</italic> FA synthesis and prompt further investigation to define new strategies to target LKB1-defective tumors.</p></sec></sec><sec id="sec5.3"><title>5.3. Role of LKB1 in response to Therapy-Induced Oxidative Stress</title><p>ROS are signaling molecules that regulate several biological processes—such as autophagy, immunity, and differentiation—through reversible thiol oxidation [<xref rid="B85" ref-type="bibr">85</xref>]. On the other hand, excessive ROS levels induce irreversible modification of proteins, alongside with oxidation of lipids and nucleic acids, thus leading to oxidative stress and cell death [<xref rid="B86" ref-type="bibr">86</xref>]. Cell fate (i.e., growth arrest, proliferation, or death) is hypothetically decided by a ROS rheostat [<xref rid="B87" ref-type="bibr">87</xref>], which, in cancer cells, is set to intermediate levels to sustain tumor growth. A further increase in ROS levels induces extensive damage to cell structures and selective elimination of cancer cells, implying modulation of redox homeostasis as a promising anticancer strategy [<xref rid="B88" ref-type="bibr">88</xref>]. Several chemotherapeutic agents and radiotherapy, indeed, kill cancer cells by increasing ROS levels beyond the toxic threshold. Cisplatin [<xref rid="B89" ref-type="bibr">89</xref>], paclitaxel and other taxanes [<xref rid="B90" ref-type="bibr">90</xref>], doxorubicin [<xref rid="B91" ref-type="bibr">91</xref>], cytarabine [<xref rid="B92" ref-type="bibr">92</xref>], and arsenic trioxide [<xref rid="B93" ref-type="bibr">93</xref>] are some examples of traditional drugs that induce lethal oxidative stress in cancer cells. Moreover, several mitochondria-targeting compounds, such as capsaicin [<xref rid="B94" ref-type="bibr">94</xref>], betulinic acid [<xref rid="B95" ref-type="bibr">95</xref>], and curcumin [<xref rid="B96" ref-type="bibr">96</xref>], induce cancer cell death by increasing ROS levels.</p><p>Several studies reported that LKB1-AMPK pathway is involved in the maintenance of redox homeostasis by contrasting ROS production and promoting ROS scavenging (<xref ref-type="fig" rid="fig1">Figure 1</xref>). Following metabolic stress, AMPK inhibits NADPH-consuming FA synthesis and increases NADPH-producing FA oxidation, thus maintaining elevated levels of NADPH, the universal electron donor used to regenerate ROS scavenging systems, leading to cancer cell survival [<xref rid="B35" ref-type="bibr">35</xref>]. ROS are able to activate AMPK, which, in turn, lowers ROS levels by inducing PGC-1<italic>α</italic>-mediated antioxidant response [<xref rid="B97" ref-type="bibr">97</xref>]. In response to ROS, AMPK activation also promotes glycolysis and pentose phosphate pathway (PPP), thus increasing NADPH levels [<xref rid="B98" ref-type="bibr">98</xref>]. Recently, it has been found that the mitochondrial NADPH pool is maintained by pathways other than the PPP [<xref rid="B99" ref-type="bibr">99</xref>]. AMPK activates Sirtuin-3 (SIRT3), which deacetylases isocitrate dehydrogenase 2 (IDH2), one of the principal contributors to NADPH production in mitochondria, thus increasing its activity [<xref rid="B100" ref-type="bibr">100</xref>]. Moreover, by increasing the activity of the tricarboxylic acid cycle and FA oxidation [<xref rid="B7" ref-type="bibr">7</xref>], AMPK could contribute to NADPH production in mitochondria through IDH2 and malic enzymes (ME) 2 and 3. LKB1 regulates oxidative stress response through p38-mediated upregulation of mitochondrial superoxide dismutase 2 (SOD2) and catalase, which scavenge ROS [<xref rid="B101" ref-type="bibr">101</xref>].</p><p>Given the established role of LKB1 and AMPK in maintaining redox homeostasis and the ability of ROS to kill cancer cells, one can speculate that functional LKB1-AMPK pathway could be a negative predictor of response to ROS-inducing therapies. Several evidences suggest that this is, in fact, the case.</p><p>In our recent work, we observed that LKB1 loss in NSCLC cells is associated with the increased expression of NADPH oxidase 1 (NOX1), leading to elevation of ROS levels (<xref ref-type="fig" rid="fig2">Figure 2</xref>) and exacerbated sensitivity to exogenous oxidative stress [<xref rid="B102" ref-type="bibr">102</xref>]. Preliminary results by our group indicate that LKB1 deficiency is associated with increased response to several ROS-inducing drugs commonly used in the clinic, such as arsenic trioxide, paclitaxel, and doxorubicin (<xref ref-type="fig" rid="fig3">Figure 3</xref>), thus suggesting that LKB1 status could predict tumor response to several chemotherapeutic regimens. Moreover, we found that LKB1-defective cancer cells undergo a decrease in reduced glutathione levels following exogenous oxidative stress and are more sensitive to cisplatin and <italic>γ</italic>-irradiation, compared with LKB1-proficient cancer cells. LKB1-defective NSCLC cells exposed to exogenous oxidative stress lose their mitochondrial membrane potential and undergo mitochondrial fragmentation, while LKB1-proficient cancer cells maintained polarized and fused mitochondria [<xref rid="B103" ref-type="bibr">103</xref>]. These results imply that LKB1-AMPK pathway exerts a protective effect towards oxidative stress, blunting the efficacy of ROS-inducing therapies. Remarkably, low-null LKB1 expression by IHC was retrospectively associated with the improved outcome in advanced NSCLC patients treated with first-line platinum-based chemotherapy [<xref rid="B104" ref-type="bibr">104</xref>]. This finding may be explained by considering the well-established role of LKB1 as a genomic sensor participating in the DNA damage response triggered by oxygen radicals. Consistently, LKB1-defective cells exposed to exogenous oxidative stress showed extensive macromolecular damage, measured as membrane lipid peroxidation, accumulation of nucleic acid oxidation marker 8-oxoguanine in mitochondrial DNA, and accumulation of DNA damage marker phosphorylated histone 2AX (<italic>γ</italic>H2AX). Strikingly, LKB1-defective cells demonstrated oxidation of mitochondrial DNA even under basal culture conditions, alongside with more fragmented mitochondria compared to LKB1-proficient cells. These findings support that LKB1 and AMPK protect cells from excessive oxidation of lipids and nucleic acids both by decreasing NOX-mediated ROS production and by increasing ROS scavenging, thus blunting the efficacy of anticancer therapies aimed at impairing redox homeostasis. In line with our findings, Li and colleagues observed that LKB1 loss in lung adenocarcinoma is associated with increased ROS levels, which drive cancer plasticity and drug resistance through transdifferentiation to squamous cell carcinoma in the <italic>KRAS</italic>-<italic>LKB1</italic>- (KL-) mutant lung cancer mouse model [<xref rid="B81" ref-type="bibr">81</xref>]. Squamous cell carcinoma, compared to adenocarcinoma, upregulated the expression of genes involved in the metabolism of glutathione and of NRF2 target genes, thus reducing DNA oxidation. Interestingly, Li and colleagues observed an inverse correlation between LKB1 expression and 8-oxoguanine levels in human NSCLC, where a proportion of cells with LKB1 loss and high 8-oxoguanine staining expressed squamous cell carcinoma markers. Reexpression of AMPK in the KL adenocarcinoma model decreased ROS levels and DNA oxidation by increasing FA oxidation-derived NADPH production, indicating the involvement of AMPK in LKB1-mediated ROS decrease, according to our findings [<xref rid="B103" ref-type="bibr">103</xref>]. Interestingly, Li and colleagues observed that treatment with phenformin in KL model resulted in the selective survival of squamous cell carcinoma clones and in transdifferentiation of adenocarcinoma to squamous cell carcinoma. Findings from Li and colleagues imply that LKB1 loss in adenocarcinoma could select for clones resistant to oxidative stress through increased activity of the transcription factor NRF2. Interestingly, KEAP1 is frequently inactivated in NSCLC (about 20% of cases [<xref rid="B105" ref-type="bibr">105</xref>]), and LKB1-defective tumors have more than sixfold increased odds of bearing KEAP1 loss compared to LKB1-proficient cancers [<xref rid="B106" ref-type="bibr">106</xref>]. Consequently, LKB1 loss is frequently associated with aberrant activation of NRF2 pathway, which drives aggressiveness and resistance to therapy. Constitutive NRF2 activation in cancer is connected with transcriptional programs aimed at increasing NADPH and glutathione levels, such as the serine synthesis pathway [<xref rid="B107" ref-type="bibr">107</xref>], which fuels mitochondrial folate cycle, the principal contributor to NADPH production in cells [<xref rid="B99" ref-type="bibr">99</xref>]. Thus, constitutive NRF2 activation is frequently coselected with LKB1 loss in human cancers to compensate for increased oxidative stress induced by lack of AMPK activation.</p></sec><sec id="sec5.4"><title>5.4. Role of LKB1-AMPK in Therapy-Induced Senescence</title><p>Different types of stress, such as oxidative or oncogenic stresses, can induce an irreversible cell cycle arrest. Permanent blockade of cell proliferation, known as senescence, is a valuable anticancer strategy that could be achieved through sublethal chemotherapy and irradiation. High doses of chemotherapeutics or radiation cause massive damage to cell structures, leading to cell death not only in cancer cells but also in highly proliferating normal cells. On the contrary, low doses of anticancer drugs or radiation lead to therapy-induced senescence (TIS) only in cancer cells, thus decreasing side effects [<xref rid="B108" ref-type="bibr">108</xref>]. Noteworthily, several chemotherapeutics, including cisplatin, doxorubicin, etoposide, and resveratrol, induce senescence in cancer cells [<xref rid="B109" ref-type="bibr">109</xref>].</p><p>Contrasting data regarding the role of AMPK on senescence induction are reported in the literature. As oxidative stress is a senescence inducer and AMPK is involved in the maintenance of redox homeostasis, it is not surprising that LKB1-AMPK pathway could prevent senescence in cancer cells [<xref rid="B110" ref-type="bibr">110</xref>]. Han and colleagues observed that hydrogen peroxide-induced senescence is associated with inhibition of AMPK. Furthermore, pharmacological activation of AMPK prevented the induction of senescence by oxidative stress, through restoration of autophagy. Interestingly, the authors observed that inhibition of autophagy through chloroquine aggravated senescence induced by hydrogen peroxide and blunted the protective role of AMPK activation. Moreover, NAD<sup>+</sup> levels are decreased in senescent cells as a consequence of NAD<sup>+</sup> salvage pathway reduction and increased NAD<sup>+</sup> consumption by PARP-1. Pharmacological activation of AMPK promoted synthesis of NAD<sup>+</sup> through salvage pathway, thus increasing the activity of NAD<sup>+</sup>-consumer SIRT1, which positively regulates autophagy. The results from Han and colleagues have important implications for cancer therapy. First, AMPK could have a protective role against TIS when the latter arises from a chemotherapeutic regimen that triggers oxidative stress. In this regard, metformin could increase the efficacy of chemotherapy, as described above, but could impair TIS, thus favouring the burden of surviving cells and tumor relapse. Second, autophagy emerges as an important escape mechanism from TIS, confirming its central role in the oncogenic properties of LKB1-AMPK pathway. The use of chloroquine or other inhibitors of lysosomal acidification in the clinic should enhance TIS, thus achieving remarkable anticancer activity.</p><p>On the other hand, the activation of SIRT1 and AMPK has been associated with the induction of senescence in colorectal carcinoma cells [<xref rid="B111" ref-type="bibr">111</xref>]. Jung and colleagues observed that aspirin induced senescence in two colorectal carcinoma cell lines, but not in normal colonic cells, through the increased expression and deacetylase activity of SIRT1 and the increased activation of AMPK. The enhanced activity of SIRT1 and AMPK was induced by a decrease of ATP levels in aspirin-treated cancer cells, as observed with irradiation. Interestingly, the authors demonstrated that knockdown of SIRT1 or inhibition of its deacetylase activity decreased aspirin-induced and irradiation-induced senescence. The same results were obtained through knockdown or inhibition of AMPK. On the contrary, activation of SIRT1 through resveratrol or of AMPK through AICAR promoted the induction of senescence. The data from Jung and colleagues are consistent with the known senescence-inducing activity of resveratrol. Thus, it is reasonable that in certain cellular contexts SIRT1 and AMPK induce senescence rather than inhibit it, as observed by Han and colleagues. The decreased levels of ATP observed in aspirin-treated cells, however, suggest that in this context autophagy could not play a central role. Although aspirin induces autophagy [<xref rid="B112" ref-type="bibr">112</xref>], it is possible that the latter was a rescue mechanism only in the context described by Han et al., thus profoundly altering the outcome of AMPK activation. The positive role of LKB1-AMPK pathway on senescence is supported by different studies. Yi and colleagues observed that low doses of metformin induced senescence of hepatoma cells through activation of AMPK [<xref rid="B113" ref-type="bibr">113</xref>]. Metformin also induced the acetylation of p53 as a consequence of AMPK-mediated inhibition of SIRT1 deacetylase activity on p53. Similarly, Liao and colleagues demonstrated that AMPK activation is involved in the metabolic alterations associated with radiation-induced senescence [<xref rid="B114" ref-type="bibr">114</xref>].</p><p>In conclusion, AMPK positively regulates TIS, implying that LKB1-proficient tumors could be more susceptible to a radiochemotherapeutic regimen that induces senescence. It should be considered, however, that AMPK-induced autophagy could be an escape mechanism that impairs TIS, thus curbing the efficacy of anticancer treatments. In this regard, a recent study provides evidence for a role of AMPK as a predictive factor of response to senescence-inducing therapies. In fact, Wang and colleagues observed that trametinib radiosensitized LKB1-defective NSCLC cells, while LKB1-proficient cells were protected by senescence through AMPK-mediated autophagy [<xref rid="B115" ref-type="bibr">115</xref>]. The central role of autophagy as a rescue mechanism—as recently confirmed by the observation of autophagy-mediated protumorigenic effects in the context of mitotic slippage-induced senescence [<xref rid="B116" ref-type="bibr">116</xref>]—suggests that the use of chloroquine in association with senescence inducers should be considered in the clinic.</p><p>Interestingly, as cancer cells could recover from senescence and senescent cells secrete soluble factors that promote tumor growth [<xref rid="B117" ref-type="bibr">117</xref>], the use of drugs that selectively kill senescent cells (known as senolytics), such as the BCL-xL inhibitor navitoclax, in combination with senescence inducers and chloroquine should be a highly effective anticancer strategy against both LKB1-proficient and defective cancers.</p></sec></sec><sec id="sec6"><title>6. Exploiting Selective Vulnerabilities in LKB1-Defective and LKB1-Proficient Tumors</title><p>A great effort focused on the identification of novel potential therapeutic targeting in highly aggressive <italic>LKB1</italic>/<italic>KRAS</italic> comutated NSCLC. Kim and colleagues tested 230,000 synthetic small molecules in a panel of 91 lung cancer-derived cell lines, identifying coatomer complex I (COPI) as necessary for the survival of <italic>LKB1</italic>/<italic>KRAS</italic> double mutant NSCLC. COPI is involved in the acidification and maturation of lysosomes, essential organelles in the maintenance of proper mitochondrial function. In fact, LKB1 inactivation and KRAS activation drive dependency on autophagy to fuel the Krebs cycle with carbon sources [<xref rid="B118" ref-type="bibr">118</xref>]. These interesting findings imply that autophagy inhibition through chloroquine, which blocks lysosome acidification, could be highly effective in killing <italic>LKB1</italic>/<italic>KRAS</italic> comutated NSCLC cells through the induction of mitochondrial dysfunction. Notably, although chloroquine has been tested in some studies aimed at targeting NSCLC [<xref rid="B119" ref-type="bibr">119</xref>–<xref rid="B122" ref-type="bibr">122</xref>], no reports in the literature refer to <italic>LKB1</italic>/<italic>KRAS</italic> mutations as a patient stratification criterion for the treatment of NSCLC.</p><p>Deoxythymidilate kinase (DTYMK) silencing has been identified as synthetically lethal with LKB1 loss in <italic>LKB1</italic>/<italic>KRAS</italic> double mutant NSCLC [<xref rid="B123" ref-type="bibr">123</xref>]. DTYMK catalyses the conversion of deoxythymidine monophosphate (dTMP) to deoxythymidine diphosphate (dTDP) and plays a fundamental role in nucleotide synthesis. Liu and colleagues demonstrated that LKB1 loss is associated with deficits in nucleotide metabolism. DTYMK inhibition in <italic>LKB1</italic>-mutated NSCLC cells leads to dUTP misincorporation in DNA, thus blocking replication. As dTMP derives from folate cycle-mediated conversion of deoxyuridine monophosphate (dUMP), hypersensitivity of <italic>LKB1</italic>-mutant tumors to antifolates, such as pemetrexed, raltitrexed, or pralatrexate, can be speculated. To the best of our knowledge, therapeutic efficacy of antifolates in <italic>LKB1</italic>-mutant lung cancer has not been evaluated in patients so far.</p><p>Another selective vulnerability in <italic>LKB1</italic>-mutated cancer cells is related to endoplasmic reticulum (ER) stress. Pharmacological induction of ER stress in <italic>LKB1</italic>/<italic>KRAS</italic> double mutant cancer cells triggers proapoptotic unfolded protein response and ROS-induced cell death [<xref rid="B124" ref-type="bibr">124</xref>]. HSP90 inhibitors and the proteasome inhibitor bortezomib are ER stress inducers currently used in the clinic. Cron and colleagues observed that proteasome inhibitors radiosensitize <italic>LKB1</italic>/<italic>KRAS</italic> double mutated NSCLC cell lines [<xref rid="B125" ref-type="bibr">125</xref>]. However, radiosensitization by bortezomib is a consequence of the accumulation of damaged proteins, which likely occurs independently from LKB1 status. It was observed that inactivation of LKB1 is associated with increased sensitivity to the HSP90 inhibitor 17-AAG [<xref rid="B126" ref-type="bibr">126</xref>–<xref rid="B128" ref-type="bibr">128</xref>]. Unfortunately, HSP90 chaperone protects LKB1 from proteasomal degradation [<xref rid="B129" ref-type="bibr">129</xref>], raising safety concerns about the exposure of normal cells to HSP90 inhibitors. Consequently, only bortezomib is a safe ER stress inducer, and more efforts should be devoted to the investigation of its efficacy in <italic>LKB1</italic>-mutated cancers.</p><p>Given the role of LKB1 in the maintenance of genomic integrity through the regulation of homologous recombination, its inactivation sensitizes cancer cells to PARP inhibitors [<xref rid="B19" ref-type="bibr">19</xref>]. PARP-1 is involved in the repair of single-strand breaks through the base excision repair (BER) pathway [<xref rid="B130" ref-type="bibr">130</xref>]. Ablation of PARP leads to the conversion of single-strand breaks to double-strand breaks during DNA replication, inducing cell death in homologous recombination-defective <italic>LKB1</italic>-mutated cancer cells. PARP inhibitors are promising anticancer drugs, some of which have been approved by the Food and Drug Administration (FDA) for the treatment of <italic>BRCA</italic>-mutated cancers. The use of PARP inhibitors in <italic>LKB1</italic>-mutated human cancers holds promise of therapeutic efficacy.</p><p>Some evidence suggests that LKB1 loss is involved in the upregulation of antiapoptotic proteins of the B-cell lymphoma 2 (BCL-2) family [<xref rid="B131" ref-type="bibr">131</xref>, <xref rid="B132" ref-type="bibr">132</xref>], implying mitochondrial priming in LKB1-defective cancer. In particular, the activation of mTORC1 in LKB1-defective tumors drives the overexpression of myeloid cell leukemia 1 (MCL1) [<xref rid="B62" ref-type="bibr">62</xref>, <xref rid="B133" ref-type="bibr">133</xref>]. In the last decade, a novel class of drugs, BH3 mimetics, was developed. BH3 mimetics mimic the structure of BH3 domain in BCL-2 family proteins, thus displacing proapoptotic BH3-only proteins from antiapoptotic proteins and inducing apoptosis. The upregulation of antiapoptotic proteins of the BCL-2 family following LKB1 loss suggests that LKB1-defective cancers could be sensitive to BH3 mimetics, particularly to MCL1 inhibitors, some of which—such as AZD5991—are currently in clinical trials for the treatment of hematological malignancies. The combination of MCL1 inhibitors with the BCL-2 specific inhibitor venetoclax should be effective against <italic>LKB1</italic>-mutated cancers and should induce a pronounced sensitization to standard chemotherapy.</p><p>Additional vulnerabilities in LKB1-defective cancers are even more speculative. The increased activation of NF-<italic>κ</italic>B and STAT3 pathways due to LKB1 loss could drive sensitivity to NF-<italic>κ</italic>B and STAT3 inhibitors in clinical trials, such as TAS4464 and TTI-101, respectively. Inhibition of these pathways should increase mitochondrial fragmentation and sensitivity to conventional therapies.</p><p>In contrast, figuring out selective vulnerabilities in LKB1-proficient cancers is not obvious. However, autophagy inhibition seems to be the most promising strategy to target drug resistance following AMPK activation, as mentioned above. In fact, the central role of ULK1 phosphorylation in the induction of angiogenesis, in the clearance of damaged mitochondria, and in maintenance of mitochondrial metabolism provides the rationale of targeting VPS34 kinase, whose activity is promoted by ULK1-mediated phosphorylation of Beclin-1. SAR405, a recently identified specific inhibitor of VPS34 kinase activity, inhibits fusion of late endosomes with lysosomes and autophagosome formation, exerting synergistic anticancer activity with the mTOR inhibitor everolimus in renal cancer cell lines [<xref rid="B134" ref-type="bibr">134</xref>]. Inhibition of autophagosomes leads to the accumulation of damaged and dysfunctional mitochondria, increasing the accumulation of mitochondrial ROS and inducing cell death [<xref rid="B135" ref-type="bibr">135</xref>]. Autophagy inhibition in LKB1-proficient tumors can be achieved with chloroquine, with some anticancer effects. However, blockade of lysosomal acidification does not impede engulfment of mitochondria in autophagosomes, which results in isolation of damaged mitochondria from the mitochondrial network. Moreover, ROS produced by damaged mitochondria inside autophagosomes must overcome two lipid membranes to reach the cytosol; thus, engulfed mitochondria release less ROS than free mitochondria.</p><p>Activated AMPK phosphorylates NRF2, thus promoting its nuclear accumulation [<xref rid="B136" ref-type="bibr">136</xref>]. The resulting activation of an antioxidant program is responsible for the resistance to oxidative stress observed in LKB1-proficient cancers. In fact, NRF2 activates the transcription of genes involved in the production of NADPH and induces cytoprotective autophagy [<xref rid="B137" ref-type="bibr">137</xref>]. Speculatively, pharmacological NRF2 inhibition should revert the resistance of LKB1-proficient tumors to ROS-inducing therapies, increasing lipid peroxidation, DNA damage, loss of mitochondrial membrane potential, and mitochondrial fragmentation, ultimately leading to cell death.</p><p>In conclusion, amongst several vulnerabilities affected by LKB1 status, dependency on cytoprotective autophagy and on NRF2-driven antioxidant response is shared by LKB1-proficient cancers and by LKB1-defective cancers driven by additional genetic alterations (i.e., activation of KRAS and loss of KEAP1).</p></sec><sec id="sec7"><title>7. Concluding Remarks</title><p>In the era of personalized medicine, the key role of LKB1 as a central sensor of stress opens new possibilities to target cancer cell metabolism, with important clinical implications.</p><p>The precise definition of LKB1 status represents a challenge for patient stratification. A comprehensive approach considering genetic, epigenetic, and LKB1 protein expression analysis should be taken into account.</p><p>Cancer cell metabolism is plastic and adaptable, and LKB1 plays a central role in its modulation (<xref ref-type="fig" rid="fig1">Figure 1</xref>). Several evidences pointed out its contextual oncogenic and tumor suppressor role. Moreover, a key function of LKB1 in modulation of tumor microenvironment is emerging. LKB1 loss is associated with a metabolic deregulation (<xref ref-type="fig" rid="fig2">Figure 2</xref>) that could be exploited from a therapeutic point of view.</p><p>Therefore, a better understanding of the pathways presided over by LKB1, through metabolomics and proteomics analyses, together with LKB1 status evaluation, is required to develop personalized treatment strategies. Such an approach could help to unravel the heterogeneity of cancer and to identify concurrent pathway alterations which could be targeted to overcome acquired resistance to molecular targeted therapies.</p></sec></body><back><ack><title>Acknowledgments</title><p>SI is supported by AIRC (IG18803).</p></ack><sec sec-type="COI-statement"><title>Conflicts of Interest</title><p>The authors declare no conflicts of interest.</p></sec><sec><title>Authors' Contributions</title><p>Ciccarese F. and Zulato E. contributed equally to this work.</p></sec><ref-list><ref id="B1"><label>1</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Jenne</surname><given-names>D. E.</given-names></name><name><surname>Reomann</surname><given-names>H.</given-names></name><name><surname>Nezu</surname><given-names>J. I.</given-names></name><etal></etal></person-group><article-title>Peutz-Jeghers syndrome is caused by mutations in a novel serine threoninekinase</article-title><source><italic toggle="yes">Nature Genetics</italic></source><year>1998</year><volume>18</volume><issue>1</issue><fpage>38</fpage><lpage>43</lpage><pub-id pub-id-type="doi">10.1038/ng0198-38</pub-id><pub-id pub-id-type="other">2-s2.0-0031974516</pub-id><pub-id pub-id-type="pmid">9425897</pub-id></element-citation></ref><ref id="B2"><label>2</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mehenni</surname><given-names>H.</given-names></name><name><surname>Gehrig</surname><given-names>C.</given-names></name><name><surname>Nezu</surname><given-names>J. I.</given-names></name><etal></etal></person-group><article-title>Loss of LKB1 kinase activity in Peutz-Jeghers syndrome, and evidence for allelic and locus heterogeneity</article-title><source><italic toggle="yes">American Journal of Human Genetics</italic></source><year>1998</year><volume>63</volume><issue>6</issue><fpage>1641</fpage><lpage>1650</lpage><pub-id pub-id-type="doi">10.1086/302159</pub-id><pub-id pub-id-type="other">2-s2.0-0032471851</pub-id><pub-id pub-id-type="pmid">9837816</pub-id></element-citation></ref><ref id="B3"><label>3</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sanchez-Cespedes</surname><given-names>M.</given-names></name><name><surname>Parrella</surname><given-names>P.</given-names></name><name><surname>Esteller</surname><given-names>M.</given-names></name><etal></etal></person-group><article-title>Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung</article-title><source><italic toggle="yes">Cancer Research</italic></source><year>2002</year><volume>62</volume><issue>13</issue><fpage>3659</fpage><lpage>3662</lpage><pub-id pub-id-type="pmid">12097271</pub-id></element-citation></ref><ref id="B4"><label>4</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Guldberg</surname><given-names>P.</given-names></name><name><surname>Straten</surname><given-names>P. .</given-names></name><name><surname>Ahrenkiel</surname><given-names>V.</given-names></name><name><surname>Seremet</surname><given-names>T.</given-names></name><name><surname>Kirkin</surname><given-names>A. F.</given-names></name><name><surname>Zeuthen</surname><given-names>J.</given-names></name></person-group><article-title>Somatic mutation of the Peutz-Jeghers syndrome gene, <italic>LKB1/STK11</italic>, in malignant melanoma</article-title><source><italic toggle="yes">Oncogene</italic></source><year>1999</year><volume>18</volume><issue>9</issue><fpage>1777</fpage><lpage>1780</lpage><pub-id pub-id-type="doi">10.1038/sj.onc.1202486</pub-id><pub-id pub-id-type="other">2-s2.0-0033522144</pub-id><pub-id pub-id-type="pmid">10208439</pub-id></element-citation></ref><ref id="B5"><label>5</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wingo</surname><given-names>S. N.</given-names></name><name><surname>Gallardo</surname><given-names>T. D.</given-names></name><name><surname>Akbay</surname><given-names>E. A.</given-names></name><etal></etal></person-group><article-title>Somatic LKB1 Mutations Promote Cervical Cancer Progressionin</article-title><source><italic toggle="yes">PLoS One</italic></source><year>2009</year><volume>4</volume><issue>4</issue><fpage>p. e5137</fpage><pub-id pub-id-type="doi">10.1371/journal.pone.0005137</pub-id><pub-id pub-id-type="other">2-s2.0-64549113040</pub-id><pub-id pub-id-type="pmid">19340305</pub-id></element-citation></ref><ref id="B6"><label>6</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Shaw</surname><given-names>R. J.</given-names></name><name><surname>Kosmatka</surname><given-names>M.</given-names></name><name><surname>Bardeesy</surname><given-names>N.</given-names></name><etal></etal></person-group><article-title>The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress</article-title><source><italic toggle="yes">Proceedings of the National Academy of Sciences of the United States of America</italic></source><year>2004</year><volume>101</volume><issue>10</issue><fpage>3329</fpage><lpage>3335</lpage><pub-id pub-id-type="doi">10.1073/pnas.0308061100</pub-id><pub-id pub-id-type="other">2-s2.0-1542618348</pub-id><pub-id pub-id-type="pmid">14985505</pub-id></element-citation></ref><ref id="B7"><label>7</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hardie</surname><given-names>D. G.</given-names></name></person-group><article-title>AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function</article-title><source><italic toggle="yes">Genes & Development</italic></source><year>2011</year><volume>25</volume><issue>18</issue><fpage>1895</fpage><lpage>1908</lpage><pub-id pub-id-type="doi">10.1101/gad.17420111</pub-id><pub-id pub-id-type="other">2-s2.0-80053035284</pub-id><pub-id pub-id-type="pmid">21937710</pub-id></element-citation></ref><ref id="B8"><label>8</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ji</surname><given-names>H.</given-names></name><name><surname>Ramsey</surname><given-names>M. R.</given-names></name><name><surname>Hayes</surname><given-names>D. N.</given-names></name><etal></etal></person-group><article-title>LKB1 modulates lung cancer differentiation and metastasis</article-title><source><italic toggle="yes">Nature</italic></source><year>2007</year><volume>448</volume><issue>7155</issue><fpage>807</fpage><lpage>810</lpage><pub-id pub-id-type="doi">10.1038/nature06030</pub-id><pub-id pub-id-type="other">2-s2.0-34547926839</pub-id><pub-id pub-id-type="pmid">17676035</pub-id></element-citation></ref><ref id="B9"><label>9</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Li</surname><given-names>J.</given-names></name><name><surname>Liu</surname><given-names>J.</given-names></name><name><surname>Li</surname><given-names>P.</given-names></name><etal></etal></person-group><article-title>Loss of LKB1 disrupts breast epithelial cell polarity and promotes breast cancer metastasis and invasion</article-title><source><italic toggle="yes">Journal of Experimental & Clinical Cancer Research</italic></source><year>2014</year><volume>33</volume><issue>1</issue><fpage>p. 70</fpage><pub-id pub-id-type="doi">10.1186/s13046-014-0070-0</pub-id><pub-id pub-id-type="other">2-s2.0-84907915831</pub-id></element-citation></ref><ref id="B10"><label>10</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Souroullas</surname><given-names>G. P.</given-names></name><name><surname>Fedoriw</surname><given-names>Y.</given-names></name><name><surname>Staudt</surname><given-names>L. M.</given-names></name><name><surname>Sharpless</surname><given-names>N. E.</given-names></name></person-group><article-title>Lkb1 deletion in murine B lymphocytes promotes cell death and cancer</article-title><source><italic toggle="yes">Experimental Hematology</italic></source><year>2017</year><volume>51</volume><fpage>63</fpage><lpage>70.e1</lpage><pub-id pub-id-type="doi">10.1016/j.exphem.2017.04.005</pub-id><pub-id pub-id-type="other">2-s2.0-85020217737</pub-id><pub-id pub-id-type="pmid">28435024</pub-id></element-citation></ref><ref id="B11"><label>11</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Liang</surname><given-names>J.</given-names></name><name><surname>Mills</surname><given-names>G. B.</given-names></name></person-group><article-title>AMPK: a contextual oncogene or tumor suppressor?</article-title><source><italic toggle="yes">Cancer Research</italic></source><year>2013</year><volume>73</volume><issue>10</issue><fpage>2929</fpage><lpage>2935</lpage><pub-id pub-id-type="doi">10.1158/0008-5472.can-12-3876</pub-id><pub-id pub-id-type="other">2-s2.0-84877851087</pub-id><pub-id pub-id-type="pmid">23644529</pub-id></element-citation></ref><ref id="B12"><label>12</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hearle</surname><given-names>N.</given-names></name><name><surname>Schumacher</surname><given-names>V.</given-names></name><name><surname>Menko</surname><given-names>F. H.</given-names></name><etal></etal></person-group><article-title>Frequency and spectrum of cancers in the Peutz-Jeghers syndrome</article-title><source><italic toggle="yes">Clinical Cancer Research</italic></source><year>2006</year><volume>12</volume><issue>10</issue><fpage>3209</fpage><lpage>3215</lpage><pub-id pub-id-type="doi">10.1158/1078-0432.ccr-06-0083</pub-id><pub-id pub-id-type="other">2-s2.0-33744782567</pub-id><pub-id pub-id-type="pmid">16707622</pub-id></element-citation></ref><ref id="B13"><label>13</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sanchez-Cespedes</surname><given-names>M.</given-names></name></person-group><article-title>A role for _LKB1_ gene in human cancer beyond the Peutz -Jeghers syndrome</article-title><source><italic toggle="yes">Oncogene</italic></source><year>2007</year><volume>26</volume><issue>57</issue><fpage>7825</fpage><lpage>7832</lpage><pub-id pub-id-type="doi">10.1038/sj.onc.1210594</pub-id><pub-id pub-id-type="other">2-s2.0-37149042642</pub-id><pub-id pub-id-type="pmid">17599048</pub-id></element-citation></ref><ref id="B14"><label>14</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>He</surname><given-names>T. Y.</given-names></name><name><surname>Tsai</surname><given-names>L. H.</given-names></name><name><surname>Huang</surname><given-names>C. C.</given-names></name><name><surname>Chou</surname><given-names>M. C.</given-names></name><name><surname>Lee</surname><given-names>H.</given-names></name></person-group><article-title>LKB1 loss at transcriptional level promotes tumor malignancy and poor patient outcomes in colorectal cancer</article-title><source><italic toggle="yes">Annals of Surgical Oncology</italic></source><year>2014</year><volume>21</volume><issue>4</issue><fpage>703</fpage><lpage>710</lpage><pub-id pub-id-type="doi">10.1245/s10434-014-3824-1</pub-id><pub-id pub-id-type="other">2-s2.0-84939873907</pub-id></element-citation></ref><ref id="B15"><label>15</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gill</surname><given-names>R. K.</given-names></name><name><surname>Yang</surname><given-names>S. H.</given-names></name><name><surname>Meerzaman</surname><given-names>D.</given-names></name><etal></etal></person-group><article-title>Frequent homozygous deletion of the _LKB1/STK11_ gene in non-small cell lung cancer</article-title><source><italic toggle="yes">Oncogene</italic></source><year>2011</year><volume>30</volume><issue>35</issue><fpage>3784</fpage><lpage>3791</lpage><pub-id pub-id-type="doi">10.1038/onc.2011.98</pub-id><pub-id pub-id-type="other">2-s2.0-80052297991</pub-id><pub-id pub-id-type="pmid">21532627</pub-id></element-citation></ref><ref id="B16"><label>16</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Caiola</surname><given-names>E.</given-names></name><name><surname>Falcetta</surname><given-names>F.</given-names></name><name><surname>Giordano</surname><given-names>S.</given-names></name><etal></etal></person-group><article-title>Co-occurring KRAS mutation/LKB1 loss in non-small cell lung cancer cells results in enhanced metabolic activity susceptible to caloric restriction: an in vitro integrated multilevel approach</article-title><source><italic toggle="yes">Journal of Experimental & Clinical Cancer Research</italic></source><year>2018</year><volume>37</volume><issue>1</issue><fpage>1</fpage><lpage>14</lpage><pub-id pub-id-type="doi">10.1186/s13046-018-0954-5</pub-id><pub-id pub-id-type="other">2-s2.0-85057600369</pub-id><pub-id pub-id-type="pmid">29301578</pub-id></element-citation></ref><ref id="B17"><label>17</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Barta</surname><given-names>J. A.</given-names></name><name><surname>McMahon</surname><given-names>S. B.</given-names></name></person-group><article-title>Lung-enriched mutations in the p53 tumor suppressor: a paradigm for tissue-specific gain of oncogenic function</article-title><source><italic toggle="yes">Molecular Cancer Research</italic></source><year>2019</year><volume>17</volume><issue>1</issue><fpage>3</fpage><lpage>9</lpage><pub-id pub-id-type="doi">10.1158/1541-7786.mcr-18-0357</pub-id><pub-id pub-id-type="other">2-s2.0-85059497596</pub-id><pub-id pub-id-type="pmid">30224539</pub-id></element-citation></ref><ref id="B18"><label>18</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Koivunen</surname><given-names>J. P.</given-names></name><name><surname>Kim</surname><given-names>J.</given-names></name><name><surname>Lee</surname><given-names>J.</given-names></name><etal></etal></person-group><article-title>Mutations in the LKB1 tumour suppressor are frequently detected in tumours from Caucasian but not Asian lung cancer patients</article-title><source><italic toggle="yes">British Journal of Cancer</italic></source><year>2008</year><volume>99</volume><issue>2</issue><fpage>245</fpage><lpage>252</lpage><pub-id pub-id-type="doi">10.1038/sj.bjc.6604469</pub-id><pub-id pub-id-type="other">2-s2.0-48249102662</pub-id><pub-id pub-id-type="pmid">18594528</pub-id></element-citation></ref><ref id="B19"><label>19</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wang</surname><given-names>Y. S.</given-names></name><name><surname>Chen</surname><given-names>J.</given-names></name><name><surname>Cui</surname><given-names>F.</given-names></name><etal></etal></person-group><article-title>LKB1 is a DNA damage response protein that regulates cellular sensitivity to PARP inhibitors</article-title><source><italic toggle="yes">Oncotarget</italic></source><year>2016</year><volume>7</volume><issue>45</issue><fpage>73389</fpage><lpage>73401</lpage><pub-id pub-id-type="doi">10.18632/oncotarget.12334</pub-id><pub-id pub-id-type="other">2-s2.0-84995745296</pub-id><pub-id pub-id-type="pmid">27705915</pub-id></element-citation></ref><ref id="B20"><label>20</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Jamal-Hanjani</surname><given-names>M.</given-names></name><name><surname>Wilson</surname><given-names>G. A.</given-names></name><name><surname>McGranahan</surname><given-names>N.</given-names></name><etal></etal></person-group><article-title>Tracking the evolution of non-small-cell lung cancer</article-title><source><italic toggle="yes">The New England Journal of Medicine</italic></source><year>2017</year><volume>376</volume><issue>22</issue><fpage>2109</fpage><lpage>2121</lpage><pub-id pub-id-type="doi">10.1056/NEJMoa1616288</pub-id><pub-id pub-id-type="other">2-s2.0-85019668203</pub-id><pub-id pub-id-type="pmid">28445112</pub-id></element-citation></ref><ref id="B21"><label>21</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hawley</surname><given-names>S. A.</given-names></name><name><surname>Boudeau</surname><given-names>J.</given-names></name><name><surname>Reid</surname><given-names>J. L.</given-names></name><etal></etal></person-group><article-title>Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade</article-title><source><italic toggle="yes">Journal of Biology</italic></source><year>2003</year><volume>2</volume><issue>4</issue><fpage>p. 28</fpage><pub-id pub-id-type="doi">10.1186/1475-4924-2-28</pub-id><pub-id pub-id-type="pmid">14511394</pub-id></element-citation></ref><ref id="B22"><label>22</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Woods</surname><given-names>A.</given-names></name><name><surname>Johnstone</surname><given-names>S. R.</given-names></name><name><surname>Dickerson</surname><given-names>K.</given-names></name><etal></etal></person-group><article-title>LKB1 is the upstream kinase in the AMP-activated protein kinase cascade</article-title><source><italic toggle="yes">Current Biology</italic></source><year>2003</year><volume>13</volume><issue>22</issue><fpage>2004</fpage><lpage>2008</lpage><pub-id pub-id-type="doi">10.1016/j.cub.2003.10.031</pub-id><pub-id pub-id-type="other">2-s2.0-10744230065</pub-id><pub-id pub-id-type="pmid">14614828</pub-id></element-citation></ref><ref id="B23"><label>23</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hardie</surname><given-names>D. G.</given-names></name><name><surname>Alessi</surname><given-names>D. R.</given-names></name></person-group><article-title>LKB1 and AMPK and the cancer-metabolism link - ten years after</article-title><source><italic toggle="yes">BMC Biology</italic></source><year>2013</year><volume>11</volume><issue>1</issue><fpage>p. 36</fpage><pub-id pub-id-type="doi">10.1186/1741-7007-11-36</pub-id><pub-id pub-id-type="other">2-s2.0-84876320551</pub-id></element-citation></ref><ref id="B24"><label>24</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hardie</surname><given-names>D. G.</given-names></name><name><surname>Ross</surname><given-names>F. A.</given-names></name><name><surname>Hawley</surname><given-names>S. A.</given-names></name></person-group><article-title>AMP-activated protein kinase: a target for drugs both ancient and modern</article-title><source><italic toggle="yes">Chemistry & Biology</italic></source><year>2012</year><volume>19</volume><issue>10</issue><fpage>1222</fpage><lpage>1236</lpage><pub-id pub-id-type="doi">10.1016/j.chembiol.2012.08.019</pub-id><pub-id pub-id-type="other">2-s2.0-84868005485</pub-id><pub-id pub-id-type="pmid">23102217</pub-id></element-citation></ref><ref id="B25"><label>25</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hawley</surname><given-names>S. A.</given-names></name><name><surname>Pan</surname><given-names>D. A.</given-names></name><name><surname>Mustard</surname><given-names>K. J.</given-names></name><etal></etal></person-group><article-title>Calmodulin-dependent protein kinase kinase-<italic>β</italic> is an alternative upstream kinase for AMP-activated protein kinase</article-title><source><italic toggle="yes">Cell Metabolism</italic></source><year>2005</year><volume>2</volume><issue>1</issue><fpage>9</fpage><lpage>19</lpage><pub-id pub-id-type="doi">10.1016/j.cmet.2005.05.009</pub-id><pub-id pub-id-type="other">2-s2.0-23044432463</pub-id><pub-id pub-id-type="pmid">16054095</pub-id></element-citation></ref><ref id="B26"><label>26</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Woods</surname><given-names>A.</given-names></name><name><surname>Dickerson</surname><given-names>K.</given-names></name><name><surname>Heath</surname><given-names>R.</given-names></name><etal></etal></person-group><article-title>Ca<sup>2+</sup>/calmodulin-dependent protein kinase kinase-<italic>β</italic> acts upstream of AMP-activated protein kinase in mammalian cells</article-title><source><italic toggle="yes">Cell Metabolism</italic></source><year>2005</year><volume>2</volume><issue>1</issue><fpage>21</fpage><lpage>33</lpage><pub-id pub-id-type="doi">10.1016/j.cmet.2005.06.005</pub-id><pub-id pub-id-type="other">2-s2.0-23044437445</pub-id><pub-id pub-id-type="pmid">16054096</pub-id></element-citation></ref><ref id="B27"><label>27</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hurley</surname><given-names>R. L.</given-names></name><name><surname>Anderson</surname><given-names>K. A.</given-names></name><name><surname>Franzone</surname><given-names>J. M.</given-names></name><name><surname>Kemp</surname><given-names>B. E.</given-names></name><name><surname>Means</surname><given-names>A. R.</given-names></name><name><surname>Witters</surname><given-names>L. A.</given-names></name></person-group><article-title>The Ca2+/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases</article-title><source><italic toggle="yes">The Journal of Biological Chemistry</italic></source><year>2005</year><volume>280</volume><issue>32</issue><fpage>29060</fpage><lpage>29066</lpage><pub-id pub-id-type="doi">10.1074/jbc.M503824200</pub-id><pub-id pub-id-type="other">2-s2.0-23844471263</pub-id><pub-id pub-id-type="pmid">15980064</pub-id></element-citation></ref><ref id="B28"><label>28</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Vara-Ciruelos</surname><given-names>D.</given-names></name><name><surname>Dandapani</surname><given-names>M.</given-names></name><name><surname>Gray</surname><given-names>A.</given-names></name><name><surname>Egbani</surname><given-names>E. O.</given-names></name><name><surname>Evans</surname><given-names>A. M.</given-names></name><name><surname>Hardie</surname><given-names>D. G.</given-names></name></person-group><article-title>Genotoxic damage activates the AMPK-<italic>α</italic>1 isoform in the nucleus via Ca2+/CaMKK2 signaling to enhance tumor cell survival</article-title><source><italic toggle="yes">Molecular Cancer Research</italic></source><year>2018</year><volume>16</volume><issue>2</issue><fpage>345</fpage><lpage>357</lpage><pub-id pub-id-type="doi">10.1158/1541-7786.mcr-17-0323</pub-id><pub-id pub-id-type="other">2-s2.0-85041472011</pub-id><pub-id pub-id-type="pmid">29133590</pub-id></element-citation></ref><ref id="B29"><label>29</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Fu</surname><given-names>X.</given-names></name><name><surname>Wan</surname><given-names>S.</given-names></name><name><surname>Lyu</surname><given-names>Y. L.</given-names></name><name><surname>Liu</surname><given-names>L. F.</given-names></name><name><surname>Qi</surname><given-names>H.</given-names></name></person-group><article-title>Etoposide induces ATM-dependent mitochondrial biogenesis through AMPK activation</article-title><source><italic toggle="yes">PLoS One</italic></source><year>2008</year><volume>3</volume><issue>4, article e2009</issue><pub-id pub-id-type="doi">10.1371/journal.pone.0002009</pub-id><pub-id pub-id-type="other">2-s2.0-44349184864</pub-id><pub-id pub-id-type="pmid">18431490</pub-id></element-citation></ref><ref id="B30"><label>30</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sanli</surname><given-names>T.</given-names></name><name><surname>Rashid</surname><given-names>A.</given-names></name><name><surname>Liu</surname><given-names>C.</given-names></name><etal></etal></person-group><article-title>Ionizing radiation activates AMP-activated kinase (AMPK): a target for radiosensitization of human cancer cells</article-title><source><italic toggle="yes">International Journal of Radiation Oncology, Biology, Physics</italic></source><year>2010</year><volume>78</volume><issue>1</issue><fpage>221</fpage><lpage>229</lpage><pub-id pub-id-type="doi">10.1016/j.ijrobp.2010.03.005</pub-id><pub-id pub-id-type="other">2-s2.0-77955917717</pub-id></element-citation></ref><ref id="B31"><label>31</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zhang</surname><given-names>C. S.</given-names></name><name><surname>Hawley</surname><given-names>S. A.</given-names></name><name><surname>Zong</surname><given-names>Y.</given-names></name><etal></etal></person-group><article-title>Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK</article-title><source><italic toggle="yes">Nature</italic></source><year>2017</year><volume>548</volume><issue>7665</issue><fpage>112</fpage><lpage>116</lpage><pub-id pub-id-type="doi">10.1038/nature23275</pub-id><pub-id pub-id-type="other">2-s2.0-85026854783</pub-id><pub-id pub-id-type="pmid">28723898</pub-id></element-citation></ref><ref id="B32"><label>32</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Carling</surname><given-names>D.</given-names></name><name><surname>Zammit</surname><given-names>V. A.</given-names></name><name><surname>Hardie</surname><given-names>D. G.</given-names></name></person-group><article-title>A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis</article-title><source><italic toggle="yes">FEBS Letters</italic></source><year>1987</year><volume>223</volume><issue>2</issue><fpage>217</fpage><lpage>222</lpage><pub-id pub-id-type="doi">10.1016/0014-5793(87)80292-2</pub-id><pub-id pub-id-type="other">2-s2.0-0023642627</pub-id><pub-id pub-id-type="pmid">2889619</pub-id></element-citation></ref><ref id="B33"><label>33</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sato</surname><given-names>R.</given-names></name><name><surname>Goldstein</surname><given-names>J. L.</given-names></name><name><surname>Brown</surname><given-names>M. S.</given-names></name></person-group><article-title>Replacement of serine-871 of hamster 3-hydroxy-3-methylglutaryl-CoA reductase prevents phosphorylation by AMP-activated kinase and blocks inhibition of sterol synthesis induced by ATP depletion</article-title><source><italic toggle="yes">Proceedings of the National Academy of Sciences of the United States of America</italic></source><year>1993</year><volume>90</volume><issue>20</issue><fpage>9261</fpage><lpage>9265</lpage><pub-id pub-id-type="doi">10.1073/pnas.90.20.9261</pub-id><pub-id pub-id-type="other">2-s2.0-0027428833</pub-id><pub-id pub-id-type="pmid">8415689</pub-id></element-citation></ref><ref id="B34"><label>34</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hardie</surname><given-names>D. G.</given-names></name><name><surname>Pan</surname><given-names>D. A.</given-names></name></person-group><article-title>Regulation of fatty acid synthesis and oxidation by the AMP-activated protein kinase</article-title><source><italic toggle="yes">Biochemical Society Transactions</italic></source><year>2002</year><volume>30</volume><fpage>1064</fpage><lpage>1070</lpage><pub-id pub-id-type="doi">10.1042/bst0301064</pub-id><pub-id pub-id-type="other">2-s2.0-0036864358</pub-id><pub-id pub-id-type="pmid">12440973</pub-id></element-citation></ref><ref id="B35"><label>35</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Jeon</surname><given-names>S. M.</given-names></name><name><surname>Chandel</surname><given-names>N. S.</given-names></name><name><surname>Hay</surname><given-names>N.</given-names></name></person-group><article-title>AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress</article-title><source><italic toggle="yes">Nature</italic></source><year>2012</year><volume>485</volume><issue>7400</issue><fpage>661</fpage><lpage>665</lpage><pub-id pub-id-type="doi">10.1038/nature11066</pub-id><pub-id pub-id-type="other">2-s2.0-84863763440</pub-id><pub-id pub-id-type="pmid">22660331</pub-id></element-citation></ref><ref id="B36"><label>36</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Shaw</surname><given-names>R. J.</given-names></name></person-group><article-title>LKB1 and AMP‐activated protein kinase control of mTOR signalling and growth</article-title><source><italic toggle="yes">Acta Physiologica (Oxford, England)</italic></source><year>2009</year><volume>196</volume><issue>1</issue><fpage>65</fpage><lpage>80</lpage><pub-id pub-id-type="doi">10.1111/j.1748-1716.2009.01972.x</pub-id><pub-id pub-id-type="other">2-s2.0-63849149937</pub-id><pub-id pub-id-type="pmid">19245654</pub-id></element-citation></ref><ref id="B37"><label>37</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Liang</surname><given-names>J.</given-names></name><name><surname>Shao</surname><given-names>S. H.</given-names></name><name><surname>Xu</surname><given-names>Z. X.</given-names></name><etal></etal></person-group><article-title>The energy sensing LKB1-AMPK pathway regulates p27<sup>kip1</sup> phosphorylation mediating the decision to enter autophagy or apoptosis</article-title><source><italic toggle="yes">Nature Cell Biology</italic></source><year>2007</year><volume>9</volume><issue>2</issue><fpage>218</fpage><lpage>224</lpage><pub-id pub-id-type="doi">10.1038/ncb1537</pub-id><pub-id pub-id-type="other">2-s2.0-33947250696</pub-id><pub-id pub-id-type="pmid">17237771</pub-id></element-citation></ref><ref id="B38"><label>38</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mihaylova</surname><given-names>M. M.</given-names></name><name><surname>Shaw</surname><given-names>R. J.</given-names></name></person-group><article-title>The AMPK signalling pathway coordinates cell growth, autophagy and metabolism</article-title><source><italic toggle="yes">Nat Cell Biol</italic></source><year>2011</year><volume>13</volume><issue>9</issue><fpage>1016</fpage><lpage>1023</lpage><pub-id pub-id-type="doi">10.1038/ncb2329</pub-id><pub-id pub-id-type="other">2-s2.0-80052511813</pub-id><pub-id pub-id-type="pmid">21892142</pub-id></element-citation></ref><ref id="B39"><label>39</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Faubert</surname><given-names>B.</given-names></name><name><surname>Boily</surname><given-names>G.</given-names></name><name><surname>Izreig</surname><given-names>S.</given-names></name><etal></etal></person-group><article-title>AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo</article-title><source><italic toggle="yes">Cell Metabolism</italic></source><year>2013</year><volume>17</volume><issue>1</issue><fpage>113</fpage><lpage>124</lpage><pub-id pub-id-type="doi">10.1016/j.cmet.2012.12.001</pub-id><pub-id pub-id-type="other">2-s2.0-84872159532</pub-id><pub-id pub-id-type="pmid">23274086</pub-id></element-citation></ref><ref id="B40"><label>40</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Herzig</surname><given-names>S.</given-names></name><name><surname>Shaw</surname><given-names>R. J.</given-names></name></person-group><article-title>AMPK: guardian of metabolism and mitochondrial homeostasis</article-title><source><italic toggle="yes">Nature Reviews Molecular Cell Biology</italic></source><year>2017</year><volume>19</volume><issue>2</issue><fpage>121</fpage><lpage>135</lpage><pub-id pub-id-type="doi">10.1038/nrm.2017.95</pub-id><pub-id pub-id-type="other">2-s2.0-85041140494</pub-id><pub-id pub-id-type="pmid">28974774</pub-id></element-citation></ref><ref id="B41"><label>41</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kim</surname><given-names>J.</given-names></name><name><surname>Kundu</surname><given-names>M.</given-names></name><name><surname>Viollet</surname><given-names>B.</given-names></name><name><surname>Guan</surname><given-names>K. L.</given-names></name></person-group><article-title>AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1</article-title><source><italic toggle="yes">Nature Cell Biology</italic></source><year>2011</year><volume>13</volume><issue>2</issue><fpage>132</fpage><lpage>141</lpage><pub-id pub-id-type="doi">10.1038/ncb2152</pub-id><pub-id pub-id-type="other">2-s2.0-79551598347</pub-id><pub-id pub-id-type="pmid">21258367</pub-id></element-citation></ref><ref id="B42"><label>42</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kim</surname><given-names>J.</given-names></name><name><surname>Yang</surname><given-names>G.</given-names></name><name><surname>Kim</surname><given-names>Y.</given-names></name><name><surname>Ha</surname><given-names>J.</given-names></name></person-group><article-title>AMPK activators: mechanisms of action and physiological activities</article-title><source><italic toggle="yes">Experimental & Molecular Medicine</italic></source><year>2016</year><volume>48</volume><issue>4</issue><fpage>p. e224</fpage><pub-id pub-id-type="doi">10.1038/emm.2016.16</pub-id><pub-id pub-id-type="other">2-s2.0-84978708804</pub-id></element-citation></ref><ref id="B43"><label>43</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gurumurthy</surname><given-names>S.</given-names></name><name><surname>Xie</surname><given-names>S. Z.</given-names></name><name><surname>Alagesan</surname><given-names>B.</given-names></name><etal></etal></person-group><article-title>The Lkb1 metabolic sensor maintains haematopoietic stem cell survival</article-title><source><italic toggle="yes">Nature</italic></source><year>2010</year><volume>468</volume><issue>7324</issue><fpage>659</fpage><lpage>663</lpage><pub-id pub-id-type="doi">10.1038/nature09572</pub-id><pub-id pub-id-type="other">2-s2.0-78649851511</pub-id><pub-id pub-id-type="pmid">21124451</pub-id></element-citation></ref><ref id="B44"><label>44</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gan</surname><given-names>B.</given-names></name><name><surname>Hu</surname><given-names>J.</given-names></name><name><surname>Jiang</surname><given-names>S.</given-names></name><etal></etal></person-group><article-title>Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells</article-title><source><italic toggle="yes">Nature</italic></source><year>2010</year><volume>468</volume><issue>7324</issue><fpage>701</fpage><lpage>704</lpage><pub-id pub-id-type="doi">10.1038/nature09595</pub-id><pub-id pub-id-type="other">2-s2.0-78649874959</pub-id><pub-id pub-id-type="pmid">21124456</pub-id></element-citation></ref><ref id="B45"><label>45</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Nakada</surname><given-names>D.</given-names></name><name><surname>Saunders</surname><given-names>T. L.</given-names></name><name><surname>Morrison</surname><given-names>S. J.</given-names></name></person-group><article-title>Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells</article-title><source><italic toggle="yes">Nature</italic></source><year>2010</year><volume>468</volume><issue>7324</issue><fpage>653</fpage><lpage>658</lpage><pub-id pub-id-type="doi">10.1038/nature09571</pub-id><pub-id pub-id-type="other">2-s2.0-78649811793</pub-id><pub-id pub-id-type="pmid">21124450</pub-id></element-citation></ref><ref id="B46"><label>46</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Alessi</surname><given-names>D. R.</given-names></name><name><surname>Sakamoto</surname><given-names>K.</given-names></name><name><surname>Bayascas</surname><given-names>J. R.</given-names></name></person-group><article-title>LKB1-dependent signaling pathways</article-title><source><italic toggle="yes">Annual Review of Biochemistry</italic></source><year>2006</year><volume>75</volume><issue>1</issue><fpage>137</fpage><lpage>163</lpage><pub-id pub-id-type="doi">10.1146/annurev.biochem.75.103004.142702</pub-id><pub-id pub-id-type="other">2-s2.0-33746353046</pub-id></element-citation></ref><ref id="B47"><label>47</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Jeon</surname><given-names>S. M.</given-names></name><name><surname>Hay</surname><given-names>N.</given-names></name></person-group><article-title>The dark face of AMPK as an essential tumor promoter</article-title><source><italic toggle="yes">Cellular Logistics</italic></source><year>2012</year><volume>2</volume><issue>4</issue><fpage>197</fpage><lpage>202</lpage><pub-id pub-id-type="doi">10.4161/cl.22651</pub-id><pub-id pub-id-type="pmid">23676995</pub-id></element-citation></ref><ref id="B48"><label>48</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lee</surname><given-names>S. W.</given-names></name><name><surname>Li</surname><given-names>C. F.</given-names></name><name><surname>Jin</surname><given-names>G.</given-names></name><etal></etal></person-group><article-title>Skp2-dependent ubiquitination and activation of LKB1 is essential for cancer cell survival under energy stress</article-title><source><italic toggle="yes">Molecular Cell</italic></source><year>2015</year><volume>57</volume><issue>6</issue><fpage>1022</fpage><lpage>1033</lpage><pub-id pub-id-type="doi">10.1016/j.molcel.2015.01.015</pub-id><pub-id pub-id-type="other">2-s2.0-84925272879</pub-id><pub-id pub-id-type="pmid">25728766</pub-id></element-citation></ref><ref id="B49"><label>49</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Trapp</surname><given-names>E. K.</given-names></name><name><surname>Majunke</surname><given-names>L.</given-names></name><name><surname>Zill</surname><given-names>B.</given-names></name><etal></etal></person-group><article-title>LKB1 pro‐oncogenic activity triggers cell survival in circulating tumor cells</article-title><source><italic toggle="yes">Molecular Oncology</italic></source><year>2017</year><volume>11</volume><issue>11</issue><fpage>1508</fpage><lpage>1526</lpage><pub-id pub-id-type="doi">10.1002/1878-0261.12111</pub-id><pub-id pub-id-type="other">2-s2.0-85030320372</pub-id><pub-id pub-id-type="pmid">28700115</pub-id></element-citation></ref><ref id="B50"><label>50</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Avtanski</surname><given-names>D. B.</given-names></name><name><surname>Nagalingam</surname><given-names>A.</given-names></name><name><surname>Bonner</surname><given-names>M. Y.</given-names></name><name><surname>Arbiser</surname><given-names>J. L.</given-names></name><name><surname>Saxena</surname><given-names>N. K.</given-names></name><name><surname>Sharma</surname><given-names>D.</given-names></name></person-group><article-title>Honokiol activates LKB1-miR-34a axis and antagonizes the oncogenic actions of leptin in breast cancer</article-title><source><italic toggle="yes">Oncotarget</italic></source><year>2015</year><volume>6</volume><issue>30</issue><fpage>29947</fpage><lpage>29962</lpage><pub-id pub-id-type="doi">10.18632/oncotarget.4937</pub-id><pub-id pub-id-type="other">2-s2.0-84945162483</pub-id><pub-id pub-id-type="pmid">26359358</pub-id></element-citation></ref><ref id="B51"><label>51</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sharma</surname><given-names>V. K.</given-names></name><name><surname>Raimondi</surname><given-names>V.</given-names></name><name><surname>Ruggero</surname><given-names>K.</given-names></name><etal></etal></person-group><article-title>Expression of miR-34a in T-cells infected by human T-lymphotropic virus 1</article-title><source><italic toggle="yes">Frontiers in Microbiology</italic></source><year>2018</year><volume>9</volume><fpage>p. 832</fpage><pub-id pub-id-type="doi">10.3389/fmicb.2018.00832</pub-id><pub-id pub-id-type="other">2-s2.0-85046662999</pub-id></element-citation></ref><ref id="B52"><label>52</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rios</surname><given-names>M.</given-names></name><name><surname>Foretz</surname><given-names>M.</given-names></name><name><surname>Viollet</surname><given-names>B.</given-names></name><etal></etal></person-group><article-title>Lipoprotein internalisation induced by oncogenic AMPK activation is essential to maintain glioblastoma cell growth</article-title><source><italic toggle="yes">European Journal of Cancer</italic></source><year>2014</year><volume>50</volume><issue>18</issue><fpage>3187</fpage><lpage>3197</lpage><pub-id pub-id-type="doi">10.1016/j.ejca.2014.09.014</pub-id><pub-id pub-id-type="other">2-s2.0-84925223796</pub-id><pub-id pub-id-type="pmid">25450947</pub-id></element-citation></ref><ref id="B53"><label>53</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Chhipa</surname><given-names>R. R.</given-names></name><name><surname>Fan</surname><given-names>Q.</given-names></name><name><surname>Anderson</surname><given-names>J.</given-names></name><etal></etal></person-group><article-title>AMP kinase promotes glioblastoma bioenergetics and tumour growth</article-title><source><italic toggle="yes">Nature Cell Biology</italic></source><year>2018</year><volume>20</volume><issue>7</issue><fpage>823</fpage><lpage>835</lpage><pub-id pub-id-type="doi">10.1038/s41556-018-0126-z</pub-id><pub-id pub-id-type="other">2-s2.0-85048675236</pub-id><pub-id pub-id-type="pmid">29915361</pub-id></element-citation></ref><ref id="B54"><label>54</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Han</surname><given-names>F.</given-names></name><name><surname>Li</surname><given-names>C. F.</given-names></name><name><surname>Cai</surname><given-names>Z.</given-names></name><etal></etal></person-group><article-title>The critical role of AMPK in driving Akt activation under stress, tumorigenesis and drug resistance</article-title><source><italic toggle="yes">Nature Communications</italic></source><year>2018</year><volume>9</volume><issue>1</issue><fpage>1</fpage><lpage>16</lpage><pub-id pub-id-type="doi">10.1038/s41467-018-07188-9</pub-id><pub-id pub-id-type="other">2-s2.0-85056277923</pub-id></element-citation></ref><ref id="B55"><label>55</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Fisher</surname><given-names>K. W.</given-names></name><name><surname>Das</surname><given-names>B.</given-names></name><name><surname>Kim</surname><given-names>H. S.</given-names></name><etal></etal></person-group><article-title>AMPK promotes aberrant PGC1<italic>β</italic> expression to support human colon tumor cell survival</article-title><source><italic toggle="yes">Molecular and Cellular Biology</italic></source><year>2015</year><volume>35</volume><issue>22</issue><fpage>3866</fpage><lpage>3879</lpage><pub-id pub-id-type="doi">10.1128/mcb.00528-15</pub-id><pub-id pub-id-type="other">2-s2.0-84944520909</pub-id><pub-id pub-id-type="pmid">26351140</pub-id></element-citation></ref><ref id="B56"><label>56</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zhang</surname><given-names>P.</given-names></name><name><surname>Lai</surname><given-names>Z. L.</given-names></name><name><surname>Chen</surname><given-names>H. F.</given-names></name><etal></etal></person-group><article-title>Curcumin synergizes with 5-fluorouracil by impairing AMPK/ULK1-dependent autophagy, AKT activity and enhancing apoptosis in colon cancer cells with tumor growth inhibition in xenograft mice</article-title><source><italic toggle="yes">Journal of Experimental & Clinical Cancer Research</italic></source><year>2017</year><volume>36</volume><issue>1</issue><fpage>1</fpage><lpage>12</lpage><pub-id pub-id-type="doi">10.1186/s13046-017-0661-7</pub-id><pub-id pub-id-type="other">2-s2.0-85039036768</pub-id><pub-id pub-id-type="pmid">28049532</pub-id></element-citation></ref><ref id="B57"><label>57</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Pei</surname><given-names>G.</given-names></name><name><surname>Luo</surname><given-names>M.</given-names></name><name><surname>Ni</surname><given-names>X.</given-names></name><etal></etal></person-group><article-title>Autophagy facilitates metadherin-induced chemotherapy resistance through the AMPK/ATG5 pathway in gastric cancer</article-title><source><italic toggle="yes">Cellular Physiology and Biochemistry</italic></source><year>2018</year><volume>46</volume><issue>2</issue><fpage>847</fpage><lpage>859</lpage><pub-id pub-id-type="doi">10.1159/000488742</pub-id><pub-id pub-id-type="other">2-s2.0-85045345390</pub-id><pub-id pub-id-type="pmid">29635244</pub-id></element-citation></ref><ref id="B58"><label>58</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Weerasekara</surname><given-names>V. K.</given-names></name><name><surname>Panek</surname><given-names>D. J.</given-names></name><name><surname>Broadbent</surname><given-names>D. G.</given-names></name><etal></etal></person-group><article-title>Metabolic-stress-induced rearrangement of the 14-3-3 Interactome Promotes Autophagy via a ULK1- and AMPK-regulated 14-3-3 Interaction with phosphorylated Atg9</article-title><source><italic toggle="yes">Molecular and Cellular Biology</italic></source><year>2014</year><volume>34</volume><issue>24</issue><fpage>4379</fpage><lpage>4388</lpage><pub-id pub-id-type="doi">10.1128/mcb.00740-14</pub-id><pub-id pub-id-type="other">2-s2.0-84918805701</pub-id><pub-id pub-id-type="pmid">25266655</pub-id></element-citation></ref><ref id="B59"><label>59</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zou</surname><given-names>Y.</given-names></name><name><surname>Wang</surname><given-names>Q.</given-names></name><name><surname>Li</surname><given-names>B.</given-names></name><name><surname>Xie</surname><given-names>B.</given-names></name><name><surname>Wang</surname><given-names>W.</given-names></name></person-group><article-title>Temozolomide induces autophagy via ATM-AMPK-ULK1 pathways in glioma</article-title><source><italic toggle="yes">Molecular Medicine Reports</italic></source><year>2014</year><volume>10</volume><issue>1</issue><fpage>411</fpage><lpage>416</lpage><pub-id pub-id-type="doi">10.3892/mmr.2014.2151</pub-id><pub-id pub-id-type="other">2-s2.0-84901457597</pub-id><pub-id pub-id-type="pmid">24737504</pub-id></element-citation></ref><ref id="B60"><label>60</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Villanueva-Paz</surname><given-names>M.</given-names></name><name><surname>Cotán</surname><given-names>D.</given-names></name><name><surname>Garrido-Maraver</surname><given-names>J.</given-names></name><etal></etal></person-group><article-title>AMPK Regulation of Cell Growth, Apoptosis, Autophagy, and Bioenergetics</article-title><source><italic toggle="yes">Experientia Supplementum</italic></source><year>2016</year><volume>107</volume><fpage>45</fpage><lpage>71</lpage><pub-id pub-id-type="doi">10.1007/978-3-319-43589-3_3</pub-id></element-citation></ref><ref id="B61"><label>61</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kroemer</surname><given-names>G.</given-names></name><name><surname>Levine</surname><given-names>B.</given-names></name></person-group><article-title>Autophagic cell death: the story of a misnomer</article-title><source><italic toggle="yes">Nature Reviews. Molecular Cell Biology</italic></source><year>2008</year><volume>9</volume><issue>12</issue><fpage>1004</fpage><lpage>1010</lpage><pub-id pub-id-type="doi">10.1038/nrm2529</pub-id><pub-id pub-id-type="other">2-s2.0-56749170677</pub-id><pub-id pub-id-type="pmid">18971948</pub-id></element-citation></ref><ref id="B62"><label>62</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Shackelford</surname><given-names>D. B.</given-names></name><name><surname>Vasquez</surname><given-names>D. S.</given-names></name><name><surname>Corbeil</surname><given-names>J.</given-names></name><etal></etal></person-group><article-title>mTOR and HIF-1 -mediated tumor metabolism in an LKB1 mouse model of Peutz-Jeghers syndrome</article-title><source><italic toggle="yes">Proceedings of the National Academy of Sciences of the United States of America</italic></source><year>2009</year><volume>106</volume><issue>27</issue><fpage>11137</fpage><lpage>11142</lpage><pub-id pub-id-type="doi">10.1073/pnas.0900465106</pub-id><pub-id pub-id-type="other">2-s2.0-67650480092</pub-id><pub-id pub-id-type="pmid">19541609</pub-id></element-citation></ref><ref id="B63"><label>63</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kim</surname><given-names>D. Y.</given-names></name><name><surname>Jung</surname><given-names>S. Y.</given-names></name><name><surname>Kim</surname><given-names>Y. J.</given-names></name><etal></etal></person-group><article-title>Hypoxia-dependent mitochondrial fission regulates endothelial progenitor cell migration, invasion, and tube formation</article-title><source><italic toggle="yes">Korean J Physiol Pharmacol</italic></source><year>2018</year><volume>22</volume><issue>2</issue><fpage>203</fpage><lpage>213</lpage><pub-id pub-id-type="doi">10.4196/kjpp.2018.22.2.203</pub-id><pub-id pub-id-type="other">2-s2.0-85043374424</pub-id><pub-id pub-id-type="pmid">29520173</pub-id></element-citation></ref><ref id="B64"><label>64</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zhou</surname><given-names>J.</given-names></name><name><surname>Li</surname><given-names>G.</given-names></name><name><surname>Zheng</surname><given-names>Y.</given-names></name><etal></etal></person-group><article-title>A novel autophagy/mitophagy inhibitor liensinine sensitizes breast cancer cells to chemotherapy through DNM1L-mediated mitochondrial fission</article-title><source><italic toggle="yes">Autophagy</italic></source><year>2015</year><volume>11</volume><issue>8</issue><fpage>1259</fpage><lpage>1279</lpage><pub-id pub-id-type="doi">10.1080/15548627.2015.1056970</pub-id><pub-id pub-id-type="other">2-s2.0-84943745182</pub-id><pub-id pub-id-type="pmid">26114658</pub-id></element-citation></ref><ref id="B65"><label>65</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Thomas</surname><given-names>K. J.</given-names></name><name><surname>Jacobson</surname><given-names>M. R.</given-names></name></person-group><article-title>Defects in mitochondrial fission protein dynamin-related protein 1 are linked to apoptotic resistance and autophagy in a lung cancer model</article-title><source><italic toggle="yes">PLoS One</italic></source><year>2012</year><volume>7</volume><issue>9, article e45319</issue><pub-id pub-id-type="doi">10.1371/journal.pone.0045319</pub-id><pub-id pub-id-type="other">2-s2.0-84866641257</pub-id><pub-id pub-id-type="pmid">23028930</pub-id></element-citation></ref><ref id="B66"><label>66</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zhang</surname><given-names>H.</given-names></name><name><surname>Liu</surname><given-names>B.</given-names></name><name><surname>Li</surname><given-names>T.</given-names></name><etal></etal></person-group><article-title>AMPK activation serves a critical role in mitochondria quality control via modulating mitophagy in the heart under chronic hypoxia</article-title><source><italic toggle="yes">International Journal of Molecular Medicine</italic></source><year>2018</year><volume>41</volume><fpage>69</fpage><lpage>76</lpage><pub-id pub-id-type="doi">10.3892/ijmm.2017.3213</pub-id><pub-id pub-id-type="other">2-s2.0-85042744797</pub-id><pub-id pub-id-type="pmid">29115402</pub-id></element-citation></ref><ref id="B67"><label>67</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Silic-Benussi</surname><given-names>M.</given-names></name><name><surname>Scattolin</surname><given-names>G.</given-names></name><name><surname>Cavallari</surname><given-names>I.</given-names></name><etal></etal></person-group><article-title>Selective killing of human T-ALL cells: an integrated approach targeting redox homeostasis and the OMA1/OPA1 axis</article-title><source><italic toggle="yes">Cell Death & Disease</italic></source><year>2018</year><volume>9</volume><issue>8</issue><fpage>1</fpage><lpage>11</lpage><pub-id pub-id-type="doi">10.1038/s41419-018-0870-9</pub-id><pub-id pub-id-type="other">2-s2.0-85050992087</pub-id><pub-id pub-id-type="pmid">29298988</pub-id></element-citation></ref><ref id="B68"><label>68</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Park</surname><given-names>E. J.</given-names></name><name><surname>Kim</surname><given-names>Y. M.</given-names></name><name><surname>Chang</surname><given-names>K. C.</given-names></name></person-group><article-title>Hemin reduces HMGB1 release by UVB in an AMPK/HO-1-dependent pathway in human keratinocytes HaCaT cells</article-title><source><italic toggle="yes">Archives of Medical Research</italic></source><year>2017</year><volume>48</volume><issue>5</issue><fpage>423</fpage><lpage>431</lpage><pub-id pub-id-type="doi">10.1016/j.arcmed.2017.10.007</pub-id><pub-id pub-id-type="other">2-s2.0-85032346383</pub-id><pub-id pub-id-type="pmid">29089150</pub-id></element-citation></ref><ref id="B69"><label>69</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Pollak</surname><given-names>M.</given-names></name></person-group><article-title>Metformin and other biguanides in oncology: advancing the research agenda</article-title><source><italic toggle="yes">Cancer Prevention Research (Philadelphia, Pa.)</italic></source><year>2010</year><volume>3</volume><issue>9</issue><fpage>1060</fpage><lpage>1065</lpage><pub-id pub-id-type="doi">10.1158/1940-6207.capr-10-0175</pub-id><pub-id pub-id-type="other">2-s2.0-77956401999</pub-id><pub-id pub-id-type="pmid">20810670</pub-id></element-citation></ref><ref id="B70"><label>70</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Owen</surname><given-names>M. R.</given-names></name><name><surname>Doran</surname><given-names>E.</given-names></name><name><surname>Halestrap</surname><given-names>A. P.</given-names></name></person-group><article-title>Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain</article-title><source><italic toggle="yes">The Biochemical Journal</italic></source><year>2000</year><volume>348</volume><issue>3</issue><fpage>607</fpage><lpage>614</lpage><pub-id pub-id-type="doi">10.1042/bj3480607</pub-id><pub-id pub-id-type="pmid">10839993</pub-id></element-citation></ref><ref id="B71"><label>71</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Shackelford</surname><given-names>D. B.</given-names></name><name><surname>Abt</surname><given-names>E.</given-names></name><name><surname>Gerken</surname><given-names>L.</given-names></name><etal></etal></person-group><article-title>LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin</article-title><source><italic toggle="yes">Cancer Cell</italic></source><year>2013</year><volume>23</volume><issue>2</issue><fpage>143</fpage><lpage>158</lpage><pub-id pub-id-type="doi">10.1016/j.ccr.2012.12.008</pub-id><pub-id pub-id-type="other">2-s2.0-84873584845</pub-id><pub-id pub-id-type="pmid">23352126</pub-id></element-citation></ref><ref id="B72"><label>72</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Moro</surname><given-names>M.</given-names></name><name><surname>Caiola</surname><given-names>E.</given-names></name><name><surname>Ganzinelli</surname><given-names>M.</given-names></name><etal></etal></person-group><article-title>Metformin Enhances Cisplatin-Induced Apoptosis and Prevents Resistance to Cisplatin in Co-mutated <italic>KRAS/LKB1</italic> NSCLC</article-title><source><italic toggle="yes">Journal of Thoracic Oncology</italic></source><year>2018</year><volume>13</volume><issue>11</issue><fpage>1692</fpage><lpage>1704</lpage><pub-id pub-id-type="doi">10.1016/j.jtho.2018.07.102</pub-id><pub-id pub-id-type="other">2-s2.0-85053715823</pub-id><pub-id pub-id-type="pmid">30149143</pub-id></element-citation></ref><ref id="B73"><label>73</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Curtarello</surname><given-names>M.</given-names></name><name><surname>Zulato</surname><given-names>E.</given-names></name><name><surname>Nardo</surname><given-names>G.</given-names></name><etal></etal></person-group><article-title>VEGF-targeted therapy stably modulates the glycolytic phenotype of tumor cells</article-title><source><italic toggle="yes">Cancer Research</italic></source><year>2015</year><volume>75</volume><issue>1</issue><fpage>120</fpage><lpage>133</lpage><pub-id pub-id-type="doi">10.1158/0008-5472.CAN-13-2037</pub-id><pub-id pub-id-type="other">2-s2.0-84920532087</pub-id><pub-id pub-id-type="pmid">25381153</pub-id></element-citation></ref><ref id="B74"><label>74</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bonanno</surname><given-names>L.</given-names></name><name><surname>Zulato</surname><given-names>E.</given-names></name><name><surname>Pavan</surname><given-names>A.</given-names></name><etal></etal></person-group><article-title>LKB1 and tumor metabolism: the interplay of immune and angiogenic microenvironment in lung cancer</article-title><source><italic toggle="yes">International Journal of Molecular Sciences</italic></source><year>2019</year><volume>20</volume><issue>8</issue><fpage>p. 1874</fpage><pub-id pub-id-type="doi">10.3390/ijms20081874</pub-id></element-citation></ref><ref id="B75"><label>75</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Indraccolo</surname><given-names>S.</given-names></name><name><surname>Randon</surname><given-names>G.</given-names></name><name><surname>Zulato</surname><given-names>E.</given-names></name><etal></etal></person-group><article-title>Metformin: a modulator of bevacizumab activity in cancer? A case report</article-title><source><italic toggle="yes">Cancer Biology and Therapy</italic></source><year>2015</year><volume>16</volume><issue>2</issue><fpage>210</fpage><lpage>214</lpage><pub-id pub-id-type="doi">10.1080/15384047.2014.1002366</pub-id><pub-id pub-id-type="other">2-s2.0-84924539920</pub-id><pub-id pub-id-type="pmid">25607951</pub-id></element-citation></ref><ref id="B76"><label>76</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Verbaanderd</surname><given-names>C.</given-names></name><name><surname>Maes</surname><given-names>H.</given-names></name><name><surname>Schaaf</surname><given-names>M. B.</given-names></name><etal></etal></person-group><article-title>Repurposing drugs in oncology (ReDO)-chloroquine and hydroxychloroquine as anti-cancer agents</article-title><source><italic toggle="yes">Ecancermedicalscience</italic></source><year>2017</year><volume>11</volume><fpage>p. 781</fpage><pub-id pub-id-type="doi">10.3332/ecancer.2017.781</pub-id><pub-id pub-id-type="other">2-s2.0-85034808566</pub-id></element-citation></ref><ref id="B77"><label>77</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Molenaar</surname><given-names>R. J.</given-names></name><name><surname>Coelen</surname><given-names>R. J. S.</given-names></name><name><surname>Khurshed</surname><given-names>M.</given-names></name><etal></etal></person-group><article-title>Study protocol of a phase IB/II clinical trial of metformin and chloroquine in patients withIDH1-mutated orIDH2-mutated solid tumours</article-title><source><italic toggle="yes">BMJ Open</italic></source><year>2017</year><volume>7</volume><issue>6, article e014961</issue><pub-id pub-id-type="doi">10.1136/bmjopen-2016-014961</pub-id><pub-id pub-id-type="other">2-s2.0-85020703622</pub-id><pub-id pub-id-type="pmid">28601826</pub-id></element-citation></ref><ref id="B78"><label>78</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Shackelford</surname><given-names>D. B.</given-names></name><name><surname>Shaw</surname><given-names>R. J.</given-names></name></person-group><article-title>The LKB1-AMPK pathway: metabolism and growth control in tumour suppression</article-title><source><italic toggle="yes">Nature Reviews. Cancer</italic></source><year>2009</year><volume>9</volume><issue>8</issue><fpage>563</fpage><lpage>575</lpage><pub-id pub-id-type="doi">10.1038/nrc2676</pub-id><pub-id pub-id-type="other">2-s2.0-67749111502</pub-id><pub-id pub-id-type="pmid">19629071</pub-id></element-citation></ref><ref id="B79"><label>79</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Contreras</surname><given-names>C. M.</given-names></name><name><surname>Akbay</surname><given-names>E. A.</given-names></name><name><surname>Gallardo</surname><given-names>T. D.</given-names></name><etal></etal></person-group><article-title>Lkb1 inactivation is sufficient to drive endometrial cancers that are aggressive yet highly responsive to mTOR inhibitor monotherapy</article-title><source><italic toggle="yes">Disease Models & Mechanisms</italic></source><year>2010</year><volume>3</volume><issue>3-4</issue><fpage>181</fpage><lpage>193</lpage><pub-id pub-id-type="doi">10.1242/dmm.004440</pub-id><pub-id pub-id-type="other">2-s2.0-77949469320</pub-id><pub-id pub-id-type="pmid">20142330</pub-id></element-citation></ref><ref id="B80"><label>80</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Liang</surname><given-names>M. C.</given-names></name><name><surname>Ma</surname><given-names>J.</given-names></name><name><surname>Chen</surname><given-names>L.</given-names></name><etal></etal></person-group><article-title>TSC1 loss synergizes with KRAS activation in lung cancer development in the mouse and confers rapamycin sensitivity</article-title><source><italic toggle="yes">Oncogene</italic></source><year>2010</year><volume>29</volume><issue>11</issue><fpage>1588</fpage><lpage>1597</lpage><pub-id pub-id-type="doi">10.1038/onc.2009.452</pub-id><pub-id pub-id-type="other">2-s2.0-77949655175</pub-id><pub-id pub-id-type="pmid">19966866</pub-id></element-citation></ref><ref id="B81"><label>81</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Li</surname><given-names>F.</given-names></name><name><surname>Han</surname><given-names>X.</given-names></name><name><surname>Li</surname><given-names>F.</given-names></name><etal></etal></person-group><article-title>LKB1 inactivation elicits a redox imbalance to modulate non-small cell lung cancer plasticity and therapeutic response</article-title><source><italic toggle="yes">Cancer Cell</italic></source><year>2015</year><volume>27</volume><issue>5</issue><fpage>698</fpage><lpage>711</lpage><pub-id pub-id-type="doi">10.1016/j.ccell.2015.04.001</pub-id><pub-id pub-id-type="other">2-s2.0-84929294757</pub-id><pub-id pub-id-type="pmid">25936644</pub-id></element-citation></ref><ref id="B82"><label>82</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Andrade-Vieira</surname><given-names>R.</given-names></name><name><surname>Goguen</surname><given-names>D.</given-names></name><name><surname>Bentley</surname><given-names>H. A.</given-names></name><name><surname>Bowen</surname><given-names>C. V.</given-names></name><name><surname>Marignani</surname><given-names>P. A.</given-names></name></person-group><article-title>Pre-clinical study of drug combinations that reduce breast cancer burden due to aberrant mTOR and metabolism promoted by LKB1 loss</article-title><source><italic toggle="yes">Oncotarget</italic></source><year>2014</year><volume>5</volume><issue>24</issue><fpage>12738</fpage><lpage>12752</lpage><pub-id pub-id-type="doi">10.18632/oncotarget.2818</pub-id><pub-id pub-id-type="other">2-s2.0-84921418431</pub-id><pub-id pub-id-type="pmid">25436981</pub-id></element-citation></ref><ref id="B83"><label>83</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cheng</surname><given-names>C.</given-names></name><name><surname>Geng</surname><given-names>F.</given-names></name><name><surname>Cheng</surname><given-names>X.</given-names></name><name><surname>Guo</surname><given-names>D.</given-names></name></person-group><article-title>Lipid metabolism reprogramming and its potential targets in cancer</article-title><source><italic toggle="yes">Cancer Commun (Lond)</italic></source><year>2018</year><volume>38</volume><issue>1</issue><fpage>1</fpage><lpage>14</lpage><pub-id pub-id-type="doi">10.1186/s40880-018-0301-4</pub-id><pub-id pub-id-type="other">2-s2.0-85055620757</pub-id><pub-id pub-id-type="pmid">29764486</pub-id></element-citation></ref><ref id="B84"><label>84</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Svensson</surname><given-names>R. U.</given-names></name><name><surname>Parker</surname><given-names>S. J.</given-names></name><name><surname>Eichner</surname><given-names>L. J.</given-names></name><etal></etal></person-group><article-title>Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models</article-title><source><italic toggle="yes">Nature Medicine</italic></source><year>2016</year><volume>22</volume><issue>10</issue><fpage>1108</fpage><lpage>1119</lpage><pub-id pub-id-type="doi">10.1038/nm.4181</pub-id><pub-id pub-id-type="other">2-s2.0-84988411272</pub-id><pub-id pub-id-type="pmid">27643638</pub-id></element-citation></ref><ref id="B85"><label>85</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sena</surname><given-names>L. A.</given-names></name><name><surname>Chandel</surname><given-names>N. S.</given-names></name></person-group><article-title>Physiological roles of mitochondrial reactive oxygen species</article-title><source><italic toggle="yes">Molecular Cell</italic></source><year>2012</year><volume>48</volume><issue>2</issue><fpage>158</fpage><lpage>167</lpage><pub-id pub-id-type="doi">10.1016/j.molcel.2012.09.025</pub-id><pub-id pub-id-type="other">2-s2.0-84868007565</pub-id><pub-id pub-id-type="pmid">23102266</pub-id></element-citation></ref><ref id="B86"><label>86</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hamanaka</surname><given-names>R. B.</given-names></name><name><surname>Chandel</surname><given-names>N. S.</given-names></name></person-group><article-title>Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes</article-title><source><italic toggle="yes">Trends in Biochemical Sciences</italic></source><year>2010</year><volume>35</volume><issue>9</issue><fpage>505</fpage><lpage>513</lpage><pub-id pub-id-type="doi">10.1016/j.tibs.2010.04.002</pub-id><pub-id pub-id-type="other">2-s2.0-77956186783</pub-id><pub-id pub-id-type="pmid">20430626</pub-id></element-citation></ref><ref id="B87"><label>87</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Maryanovich</surname><given-names>M.</given-names></name><name><surname>Gross</surname><given-names>A.</given-names></name></person-group><article-title>A ROS rheostat for cell fate regulation</article-title><source><italic toggle="yes">Trends in Cell Biology</italic></source><year>2013</year><volume>23</volume><issue>3</issue><fpage>129</fpage><lpage>134</lpage><pub-id pub-id-type="doi">10.1016/j.tcb.2012.09.007</pub-id><pub-id pub-id-type="other">2-s2.0-84874260968</pub-id><pub-id pub-id-type="pmid">23117019</pub-id></element-citation></ref><ref id="B88"><label>88</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Trachootham</surname><given-names>D.</given-names></name><name><surname>Alexandre</surname><given-names>J.</given-names></name><name><surname>Huang</surname><given-names>P.</given-names></name></person-group><article-title>Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach?</article-title><source><italic toggle="yes">Nature Reviews. Drug Discovery</italic></source><year>2009</year><volume>8</volume><issue>7</issue><fpage>579</fpage><lpage>591</lpage><pub-id pub-id-type="doi">10.1038/nrd2803</pub-id><pub-id pub-id-type="other">2-s2.0-67650071137</pub-id><pub-id pub-id-type="pmid">19478820</pub-id></element-citation></ref><ref id="B89"><label>89</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Casares</surname><given-names>C.</given-names></name><name><surname>Ramírez-Camacho</surname><given-names>R.</given-names></name><name><surname>Trinidad</surname><given-names>A.</given-names></name><name><surname>Roldán</surname><given-names>A.</given-names></name><name><surname>Jorge</surname><given-names>E.</given-names></name><name><surname>García-Berrocal</surname><given-names>J. R.</given-names></name></person-group><article-title>Reactive oxygen species in apoptosis induced by cisplatin: review of physiopathological mechanisms in animal models</article-title><source><italic toggle="yes">European Archives of Oto-Rhino-Laryngology</italic></source><year>2012</year><volume>269</volume><issue>12</issue><fpage>2455</fpage><lpage>2459</lpage><pub-id pub-id-type="doi">10.1007/s00405-012-2029-0</pub-id><pub-id pub-id-type="other">2-s2.0-84871284072</pub-id><pub-id pub-id-type="pmid">22584749</pub-id></element-citation></ref><ref id="B90"><label>90</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Alexandre</surname><given-names>J.</given-names></name><name><surname>Hu</surname><given-names>Y.</given-names></name><name><surname>Lu</surname><given-names>W.</given-names></name><name><surname>Pelicano</surname><given-names>H.</given-names></name><name><surname>Huang</surname><given-names>P.</given-names></name></person-group><article-title>Novel action of paclitaxel against cancer cells: bystander effect mediated by reactive oxygen species</article-title><source><italic toggle="yes">Cancer Research</italic></source><year>2007</year><volume>67</volume><issue>8</issue><fpage>3512</fpage><lpage>3517</lpage><pub-id pub-id-type="doi">10.1158/0008-5472.can-06-3914</pub-id><pub-id pub-id-type="other">2-s2.0-34248582844</pub-id><pub-id pub-id-type="pmid">17440056</pub-id></element-citation></ref><ref id="B91"><label>91</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tsang</surname><given-names>W. P.</given-names></name><name><surname>Chau</surname><given-names>S. P.</given-names></name><name><surname>Kong</surname><given-names>S. K.</given-names></name><name><surname>Fung</surname><given-names>K. P.</given-names></name><name><surname>Kwok</surname><given-names>T. T.</given-names></name></person-group><article-title>Reactive oxygen species mediate doxorubicin induced p53-independent apoptosis</article-title><source><italic toggle="yes">Life Sciences</italic></source><year>2003</year><volume>73</volume><issue>16</issue><fpage>2047</fpage><lpage>2058</lpage><pub-id pub-id-type="doi">10.1016/s0024-3205(03)00566-6</pub-id><pub-id pub-id-type="other">2-s2.0-0042705073</pub-id><pub-id pub-id-type="pmid">12899928</pub-id></element-citation></ref><ref id="B92"><label>92</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Iacobini</surname><given-names>M.</given-names></name><name><surname>Menichelli</surname><given-names>A.</given-names></name><name><surname>Palumbo</surname><given-names>G.</given-names></name><name><surname>Multari</surname><given-names>G.</given-names></name><name><surname>Werner</surname><given-names>B.</given-names></name><name><surname>del Principe</surname><given-names>D.</given-names></name></person-group><article-title>Involvement of oxygen radicals in cytarabine-induced apoptosis in human polymorphonuclear cells<sup>1</sup></article-title><source><italic toggle="yes">Biochemical Pharmacology</italic></source><year>2001</year><volume>61</volume><issue>8</issue><fpage>1033</fpage><lpage>1040</lpage><pub-id pub-id-type="doi">10.1016/s0006-2952(01)00548-2</pub-id><pub-id pub-id-type="other">2-s2.0-0035871907</pub-id><pub-id pub-id-type="pmid">11286995</pub-id></element-citation></ref><ref id="B93"><label>93</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wu</surname><given-names>B.</given-names></name><name><surname>Tan</surname><given-names>M.</given-names></name><name><surname>Cai</surname><given-names>W.</given-names></name><name><surname>Wang</surname><given-names>B.</given-names></name><name><surname>He</surname><given-names>P.</given-names></name><name><surname>Zhang</surname><given-names>X.</given-names></name></person-group><article-title>Arsenic trioxide induces autophagic cell death in osteosarcoma cells via the ROS-TFEB signaling pathway</article-title><source><italic toggle="yes">Biochemical and Biophysical Research Communications</italic></source><year>2018</year><volume>496</volume><issue>1</issue><fpage>167</fpage><lpage>175</lpage><pub-id pub-id-type="doi">10.1016/j.bbrc.2018.01.018</pub-id><pub-id pub-id-type="other">2-s2.0-85040018031</pub-id><pub-id pub-id-type="pmid">29307831</pub-id></element-citation></ref><ref id="B94"><label>94</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zhang</surname><given-names>R.</given-names></name><name><surname>Humphreys</surname><given-names>I.</given-names></name><name><surname>Sahu</surname><given-names>R. P.</given-names></name><name><surname>Shi</surname><given-names>Y.</given-names></name><name><surname>Srivastava</surname><given-names>S. K.</given-names></name></person-group><article-title>In vitro and in vivo induction of apoptosis by capsaicin in pancreatic cancer cells is mediated through ROS generation and mitochondrial death pathway</article-title><source><italic toggle="yes">Apoptosis</italic></source><year>2008</year><volume>13</volume><issue>12</issue><fpage>1465</fpage><lpage>1478</lpage><pub-id pub-id-type="doi">10.1007/s10495-008-0278-6</pub-id><pub-id pub-id-type="other">2-s2.0-56349151331</pub-id><pub-id pub-id-type="pmid">19002586</pub-id></element-citation></ref><ref id="B95"><label>95</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wang</surname><given-names>X.</given-names></name><name><surname>Lu</surname><given-names>X.</given-names></name><name><surname>Zhu</surname><given-names>R.</given-names></name><etal></etal></person-group><article-title>Betulinic acid induces apoptosis in differentiated PC12 cells via ROS-mediated mitochondrial pathway</article-title><source><italic toggle="yes">Neurochemical Research</italic></source><year>2017</year><volume>42</volume><issue>4</issue><fpage>1130</fpage><lpage>1140</lpage><pub-id pub-id-type="doi">10.1007/s11064-016-2147-y</pub-id><pub-id pub-id-type="other">2-s2.0-85010790623</pub-id><pub-id pub-id-type="pmid">28124213</pub-id></element-citation></ref><ref id="B96"><label>96</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gandhy</surname><given-names>S. U.</given-names></name><name><surname>Kim</surname><given-names>K.</given-names></name><name><surname>Larsen</surname><given-names>L.</given-names></name><name><surname>Rosengren</surname><given-names>R. J.</given-names></name><name><surname>Safe</surname><given-names>S.</given-names></name></person-group><article-title>Curcumin and synthetic analogs induce reactive oxygen species and decreases specificity protein (Sp) transcription factors by targeting microRNAs</article-title><source><italic toggle="yes">BMC Cancer</italic></source><year>2012</year><volume>12</volume><issue>1</issue><fpage>p. 564</fpage><pub-id pub-id-type="doi">10.1186/1471-2407-12-564</pub-id></element-citation></ref><ref id="B97"><label>97</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rabinovitch</surname><given-names>R. C.</given-names></name><name><surname>Samborska</surname><given-names>B.</given-names></name><name><surname>Faubert</surname><given-names>B.</given-names></name><etal></etal></person-group><article-title>AMPK maintains cellular metabolic homeostasis through regulation of mitochondrial reactive oxygen species</article-title><source><italic toggle="yes">Cell Reports</italic></source><year>2017</year><volume>21</volume><issue>1</issue><fpage>1</fpage><lpage>9</lpage><pub-id pub-id-type="doi">10.1016/j.celrep.2017.09.026</pub-id><pub-id pub-id-type="other">2-s2.0-85030714063</pub-id><pub-id pub-id-type="pmid">28978464</pub-id></element-citation></ref><ref id="B98"><label>98</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wu</surname><given-names>S. B.</given-names></name><name><surname>Wei</surname><given-names>Y. H.</given-names></name></person-group><article-title>AMPK-mediated increase of glycolysis as an adaptive response to oxidative stress in human cells: implication of the cell survival in mitochondrial diseases</article-title><source><italic toggle="yes">Biochimica et Biophysica Acta</italic></source><year>2012</year><volume>1822</volume><issue>2</issue><fpage>233</fpage><lpage>247</lpage><pub-id pub-id-type="doi">10.1016/j.bbadis.2011.09.014</pub-id><pub-id pub-id-type="other">2-s2.0-83255189409</pub-id><pub-id pub-id-type="pmid">22001850</pub-id></element-citation></ref><ref id="B99"><label>99</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ciccarese</surname><given-names>F.</given-names></name><name><surname>Ciminale</surname><given-names>V.</given-names></name></person-group><article-title>Escaping death: mitochondrial redox homeostasis in cancer cells</article-title><source><italic toggle="yes">Frontiers in Oncology</italic></source><year>2017</year><volume>7</volume><fpage>p. 117</fpage><pub-id pub-id-type="doi">10.3389/fonc.2017.00117</pub-id><pub-id pub-id-type="other">2-s2.0-85020904487</pub-id></element-citation></ref><ref id="B100"><label>100</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yu</surname><given-names>W.</given-names></name><name><surname>Dittenhafer-Reed</surname><given-names>K. E.</given-names></name><name><surname>Denu</surname><given-names>J. M.</given-names></name></person-group><article-title>SIRT3 protein deacetylates isocitrate dehydrogenase 2 (IDH2) and regulates mitochondrial redox status</article-title><source><italic toggle="yes">The Journal of Biological Chemistry</italic></source><year>2012</year><volume>287</volume><issue>17</issue><fpage>14078</fpage><lpage>14086</lpage><pub-id pub-id-type="doi">10.1074/jbc.M112.355206</pub-id><pub-id pub-id-type="other">2-s2.0-84859951790</pub-id><pub-id pub-id-type="pmid">22416140</pub-id></element-citation></ref><ref id="B101"><label>101</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Xu</surname><given-names>H. G.</given-names></name><name><surname>Zhai</surname><given-names>Y. X.</given-names></name><name><surname>Chen</surname><given-names>J.</given-names></name><etal></etal></person-group><article-title>LKB1 reduces ROS-mediated cell damage via activation of p38</article-title><source><italic toggle="yes">Oncogene</italic></source><year>2015</year><volume>34</volume><issue>29</issue><fpage>3848</fpage><lpage>3859</lpage><pub-id pub-id-type="doi">10.1038/onc.2014.315</pub-id><pub-id pub-id-type="other">2-s2.0-84937389768</pub-id><pub-id pub-id-type="pmid">25263448</pub-id></element-citation></ref><ref id="B102"><label>102</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zulato</surname><given-names>E.</given-names></name><name><surname>Ciccarese</surname><given-names>F.</given-names></name><name><surname>Nardo</surname><given-names>G.</given-names></name><etal></etal></person-group><article-title>Involvement of NADPH oxidase 1 in liver kinase B1-mediated effects on tumor angiogenesis and growth</article-title><source><italic toggle="yes">Frontiers in Oncology</italic></source><year>2018</year><volume>8</volume><fpage>p. 195</fpage><pub-id pub-id-type="doi">10.3389/fonc.2018.00195</pub-id><pub-id pub-id-type="other">2-s2.0-85048199378</pub-id></element-citation></ref><ref id="B103"><label>103</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zulato</surname><given-names>E.</given-names></name><name><surname>Ciccarese</surname><given-names>F.</given-names></name><name><surname>Agnusdei</surname><given-names>V.</given-names></name><etal></etal></person-group><article-title>LKB1 loss is associated with glutathione deficiency under oxidative stress and sensitivity of cancer cells to cytotoxic drugs and <italic>γ</italic>-irradiation</article-title><source><italic toggle="yes">Biochemical Pharmacology</italic></source><year>2018</year><volume>156</volume><fpage>479</fpage><lpage>490</lpage><pub-id pub-id-type="doi">10.1016/j.bcp.2018.09.019</pub-id><pub-id pub-id-type="other">2-s2.0-85053749679</pub-id><pub-id pub-id-type="pmid">30222967</pub-id></element-citation></ref><ref id="B104"><label>104</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bonanno</surname><given-names>L.</given-names></name><name><surname>de Paoli</surname><given-names>A.</given-names></name><name><surname>Zulato</surname><given-names>E.</given-names></name><etal></etal></person-group><article-title>LKB1 expression correlates with increased survival in patients with advanced non-small cell lung cancer treated with chemotherapy and bevacizumab</article-title><source><italic toggle="yes">Clinical Cancer Research</italic></source><year>2017</year><volume>23</volume><issue>13</issue><fpage>3316</fpage><lpage>3324</lpage><pub-id pub-id-type="doi">10.1158/1078-0432.CCR-16-2410</pub-id><pub-id pub-id-type="other">2-s2.0-85021755980</pub-id><pub-id pub-id-type="pmid">28119362</pub-id></element-citation></ref><ref id="B105"><label>105</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Singh</surname><given-names>A.</given-names></name><name><surname>Misra</surname><given-names>V.</given-names></name><name><surname>Thimmulappa</surname><given-names>R. K.</given-names></name><etal></etal></person-group><article-title>Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer</article-title><source><italic toggle="yes">PLoS Medicine</italic></source><year>2006</year><volume>3</volume><issue>10, article e420</issue><pub-id pub-id-type="doi">10.1371/journal.pmed.0030420</pub-id><pub-id pub-id-type="other">2-s2.0-33750885385</pub-id><pub-id pub-id-type="pmid">17020408</pub-id></element-citation></ref><ref id="B106"><label>106</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kaufman</surname><given-names>J. M.</given-names></name><name><surname>Amann</surname><given-names>J. M.</given-names></name><name><surname>Park</surname><given-names>K.</given-names></name><etal></etal></person-group><article-title>_LKB1_ Loss Induces Characteristic Patterns of Gene Expression in Human Tumors Associated with NRF2 Activation and Attenuation of PI3K-AKT</article-title><source><italic toggle="yes">Journal of Thoracic Oncology</italic></source><year>2014</year><volume>9</volume><issue>6</issue><fpage>794</fpage><lpage>804</lpage><pub-id pub-id-type="doi">10.1097/jto.0000000000000173</pub-id><pub-id pub-id-type="other">2-s2.0-84901401518</pub-id><pub-id pub-id-type="pmid">24828662</pub-id></element-citation></ref><ref id="B107"><label>107</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kitamura</surname><given-names>H.</given-names></name><name><surname>Motohashi</surname><given-names>H.</given-names></name></person-group><article-title>NRF2 addiction in cancer cells</article-title><source><italic toggle="yes">Cancer Science</italic></source><year>2018</year><volume>109</volume><issue>4</issue><fpage>900</fpage><lpage>911</lpage><pub-id pub-id-type="doi">10.1111/cas.13537</pub-id><pub-id pub-id-type="other">2-s2.0-85043479323</pub-id><pub-id pub-id-type="pmid">29450944</pub-id></element-citation></ref><ref id="B108"><label>108</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lee</surname><given-names>S.</given-names></name><name><surname>Lee</surname><given-names>J. S.</given-names></name></person-group><article-title>Cellular senescence: a promising strategy for cancer therapy</article-title><source><italic toggle="yes">BMB Reports</italic></source><year>2019</year><volume>52</volume><issue>1</issue><fpage>35</fpage><lpage>41</lpage><pub-id pub-id-type="doi">10.5483/BMBRep.2019.52.1.294</pub-id><pub-id pub-id-type="other">2-s2.0-85060960151</pub-id><pub-id pub-id-type="pmid">30526771</pub-id></element-citation></ref><ref id="B109"><label>109</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ewald</surname><given-names>J. A.</given-names></name><name><surname>Desotelle</surname><given-names>J. A.</given-names></name><name><surname>Wilding</surname><given-names>G.</given-names></name><name><surname>Jarrard</surname><given-names>D. F.</given-names></name></person-group><article-title>Therapy-induced senescence in cancer</article-title><source><italic toggle="yes">Journal of the National Cancer Institute</italic></source><year>2010</year><volume>102</volume><issue>20</issue><fpage>1536</fpage><lpage>1546</lpage><pub-id pub-id-type="doi">10.1093/jnci/djq364</pub-id><pub-id pub-id-type="other">2-s2.0-77958590185</pub-id><pub-id pub-id-type="pmid">20858887</pub-id></element-citation></ref><ref id="B110"><label>110</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Han</surname><given-names>X.</given-names></name><name><surname>Tai</surname><given-names>H.</given-names></name><name><surname>Wang</surname><given-names>X.</given-names></name><etal></etal></person-group><article-title>AMPK activation protects cells from oxidative stress‐induced senescence via autophagic flux restoration and intracellular NAD+ elevation</article-title><source><italic toggle="yes">Aging Cell</italic></source><year>2016</year><volume>15</volume><issue>3</issue><fpage>416</fpage><lpage>427</lpage><pub-id pub-id-type="doi">10.1111/acel.12446</pub-id><pub-id pub-id-type="other">2-s2.0-84964706600</pub-id><pub-id pub-id-type="pmid">26890602</pub-id></element-citation></ref><ref id="B111"><label>111</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Jung</surname><given-names>Y. R.</given-names></name><name><surname>Kim</surname><given-names>E. J.</given-names></name><name><surname>Choi</surname><given-names>H. J.</given-names></name><etal></etal></person-group><article-title>Aspirin targets SIRT1 and AMPK to induce senescence of colorectal carcinoma cells</article-title><source><italic toggle="yes">Molecular Pharmacology</italic></source><year>2015</year><volume>88</volume><issue>4</issue><fpage>708</fpage><lpage>719</lpage><pub-id pub-id-type="doi">10.1124/mol.115.098616</pub-id><pub-id pub-id-type="other">2-s2.0-84946761872</pub-id><pub-id pub-id-type="pmid">26219912</pub-id></element-citation></ref><ref id="B112"><label>112</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Castoldi</surname><given-names>F.</given-names></name><name><surname>Pietrocola</surname><given-names>F.</given-names></name><name><surname>Maiuri</surname><given-names>M. C.</given-names></name><name><surname>Kroemer</surname><given-names>G.</given-names></name></person-group><article-title>Aspirin induces autophagy via inhibition of the acetyltransferase EP300</article-title><source><italic toggle="yes">Oncotarget</italic></source><year>2018</year><volume>9</volume><issue>37</issue><fpage>24574</fpage><lpage>24575</lpage><pub-id pub-id-type="doi">10.18632/oncotarget.25364</pub-id><pub-id pub-id-type="other">2-s2.0-85046960196</pub-id><pub-id pub-id-type="pmid">29872488</pub-id></element-citation></ref><ref id="B113"><label>113</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yi</surname><given-names>G.</given-names></name><name><surname>He</surname><given-names>Z.</given-names></name><name><surname>Zhou</surname><given-names>X.</given-names></name><etal></etal></person-group><article-title>Low concentration of metformin induces a p53-dependent senescence in hepatoma cells via activation of the AMPK pathway</article-title><source><italic toggle="yes">International Journal of Oncology</italic></source><year>2013</year><volume>43</volume><issue>5</issue><fpage>1503</fpage><lpage>1510</lpage><pub-id pub-id-type="doi">10.3892/ijo.2013.2077</pub-id><pub-id pub-id-type="other">2-s2.0-84885084347</pub-id><pub-id pub-id-type="pmid">23982736</pub-id></element-citation></ref><ref id="B114"><label>114</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Liao</surname><given-names>E. C.</given-names></name><name><surname>Hsu</surname><given-names>Y. T.</given-names></name><name><surname>Chuah</surname><given-names>Q. Y.</given-names></name><etal></etal></person-group><article-title>Radiation induces senescence and a bystander effect through metabolic alterations</article-title><source><italic toggle="yes">Cell Death & Disease</italic></source><year>2014</year><volume>5</volume><issue>5, article e1255</issue><pub-id pub-id-type="doi">10.1038/cddis.2014.220</pub-id><pub-id pub-id-type="other">2-s2.0-84907958755</pub-id></element-citation></ref><ref id="B115"><label>115</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wang</surname><given-names>Y.</given-names></name><name><surname>Li</surname><given-names>N.</given-names></name><name><surname>Jiang</surname><given-names>W.</given-names></name><etal></etal></person-group><article-title>Mutant LKB1 confers enhanced radiosensitization in combination with trametinib in KRAS-mutant non-small cell lung cancer</article-title><source><italic toggle="yes">Clinical Cancer Research</italic></source><year>2018</year><volume>24</volume><issue>22</issue><fpage>5744</fpage><lpage>5756</lpage><pub-id pub-id-type="doi">10.1158/1078-0432.ccr-18-1489</pub-id><pub-id pub-id-type="other">2-s2.0-85056592239</pub-id><pub-id pub-id-type="pmid">30068711</pub-id></element-citation></ref><ref id="B116"><label>116</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Jakhar</surname><given-names>R.</given-names></name><name><surname>Luijten</surname><given-names>M. N. H.</given-names></name><name><surname>Wong</surname><given-names>A. X. F.</given-names></name><etal></etal></person-group><article-title>Autophagy governs protumorigenic effects of mitotic slippage-induced senescence</article-title><source><italic toggle="yes">Molecular Cancer Research</italic></source><year>2018</year><volume>16</volume><issue>11</issue><fpage>1625</fpage><lpage>1640</lpage><pub-id pub-id-type="doi">10.1158/1541-7786.mcr-18-0024</pub-id><pub-id pub-id-type="other">2-s2.0-85055906089</pub-id><pub-id pub-id-type="pmid">30037855</pub-id></element-citation></ref><ref id="B117"><label>117</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Short</surname><given-names>S.</given-names></name><name><surname>Fielder</surname><given-names>E.</given-names></name><name><surname>Miwa</surname><given-names>S.</given-names></name><name><surname>von Zglinicki</surname><given-names>T.</given-names></name></person-group><article-title>Senolytics and senostatics as adjuvant tumour therapy</article-title><source><italic toggle="yes">eBioMedicine</italic></source><year>2019</year><volume>41</volume><fpage>683</fpage><lpage>692</lpage><pub-id pub-id-type="doi">10.1016/j.ebiom.2019.01.056</pub-id><pub-id pub-id-type="other">2-s2.0-85061026548</pub-id><pub-id pub-id-type="pmid">30737084</pub-id></element-citation></ref><ref id="B118"><label>118</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kim</surname><given-names>H. S.</given-names></name><name><surname>Mendiratta</surname><given-names>S.</given-names></name><name><surname>Kim</surname><given-names>J.</given-names></name><etal></etal></person-group><article-title>Systematic identification of molecular subtype-selective vulnerabilities in non-small-cell lung cancer</article-title><source><italic toggle="yes">Cell</italic></source><year>2013</year><volume>155</volume><issue>3</issue><fpage>552</fpage><lpage>566</lpage><pub-id pub-id-type="doi">10.1016/j.cell.2013.09.041</pub-id><pub-id pub-id-type="other">2-s2.0-84886787846</pub-id><pub-id pub-id-type="pmid">24243015</pub-id></element-citation></ref><ref id="B119"><label>119</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wang</surname><given-names>Y.</given-names></name><name><surname>Peng</surname><given-names>R. Q.</given-names></name><name><surname>Li</surname><given-names>D. D.</given-names></name><etal></etal></person-group><article-title>Chloroquine enhances the cytotoxicity of topotecan by inhibiting autophagy in lung cancer cells</article-title><source><italic toggle="yes">Chinese Journal of Cancer</italic></source><year>2011</year><volume>30</volume><issue>10</issue><fpage>690</fpage><lpage>700</lpage><pub-id pub-id-type="doi">10.5732/cjc.011.10056</pub-id><pub-id pub-id-type="other">2-s2.0-80054764087</pub-id><pub-id pub-id-type="pmid">21959046</pub-id></element-citation></ref><ref id="B120"><label>120</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Liu</surname><given-names>L.</given-names></name><name><surname>Han</surname><given-names>C.</given-names></name><name><surname>Yu</surname><given-names>H.</given-names></name><etal></etal></person-group><article-title>Chloroquine inhibits cell growth in human A549 lung cancer cells by blocking autophagy and inducing mitochondrial‑mediated apoptosis</article-title><source><italic toggle="yes">Oncology Reports</italic></source><year>2018</year><volume>39</volume><fpage>2807</fpage><lpage>2816</lpage><pub-id pub-id-type="doi">10.3892/or.2018.6363</pub-id><pub-id pub-id-type="other">2-s2.0-85046371624</pub-id><pub-id pub-id-type="pmid">29658606</pub-id></element-citation></ref><ref id="B121"><label>121</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Liu</surname><given-names>F.</given-names></name><name><surname>Shang</surname><given-names>Y.</given-names></name><name><surname>Chen</surname><given-names>S. Z.</given-names></name></person-group><article-title>Chloroquine potentiates the anti-cancer effect of lidamycin on non-small cell lung cancer cells _in vitro_</article-title><source><italic toggle="yes">Acta Pharmacologica Sinica</italic></source><year>2014</year><volume>35</volume><issue>5</issue><fpage>645</fpage><lpage>652</lpage><pub-id pub-id-type="doi">10.1038/aps.2014.3</pub-id><pub-id pub-id-type="other">2-s2.0-84927173417</pub-id><pub-id pub-id-type="pmid">24727941</pub-id></element-citation></ref><ref id="B122"><label>122</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zou</surname><given-names>Y.</given-names></name><name><surname>Ling</surname><given-names>Y. H.</given-names></name><name><surname>Sironi</surname><given-names>J.</given-names></name><name><surname>Schwartz</surname><given-names>E. L.</given-names></name><name><surname>Perez-Soler</surname><given-names>R.</given-names></name><name><surname>Piperdi</surname><given-names>B.</given-names></name></person-group><article-title>The Autophagy Inhibitor Chloroquine Overcomes the Innate Resistance of Wild- Type EGFR Non-Small-Cell Lung Cancer Cells to Erlotinib</article-title><source><italic toggle="yes">Journal of Thoracic Oncology</italic></source><year>2013</year><volume>8</volume><issue>6</issue><fpage>693</fpage><lpage>702</lpage><pub-id pub-id-type="doi">10.1097/JTO.0b013e31828c7210</pub-id><pub-id pub-id-type="other">2-s2.0-84879497873</pub-id><pub-id pub-id-type="pmid">23575415</pub-id></element-citation></ref><ref id="B123"><label>123</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Liu</surname><given-names>Y.</given-names></name><name><surname>Marks</surname><given-names>K.</given-names></name><name><surname>Cowley</surname><given-names>G. S.</given-names></name><etal></etal></person-group><article-title>Metabolic and functional genomic studies identify deoxythymidylate kinase as a target in LKB1-mutant lung cancer</article-title><source><italic toggle="yes">Cancer Discovery</italic></source><year>2013</year><volume>3</volume><issue>8</issue><fpage>870</fpage><lpage>879</lpage><pub-id pub-id-type="doi">10.1158/2159-8290.cd-13-0015</pub-id><pub-id pub-id-type="other">2-s2.0-84881508779</pub-id><pub-id pub-id-type="pmid">23715154</pub-id></element-citation></ref><ref id="B124"><label>124</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Inge</surname><given-names>L. J.</given-names></name><name><surname>Friel</surname><given-names>J. M.</given-names></name><name><surname>Richer</surname><given-names>A. L.</given-names></name><etal></etal></person-group><article-title>LKB1 inactivation sensitizes non-small cell lung cancer to pharmacological aggravation of ER stress</article-title><source><italic toggle="yes">Cancer Letters</italic></source><year>2014</year><volume>352</volume><issue>2</issue><fpage>187</fpage><lpage>195</lpage><pub-id pub-id-type="doi">10.1016/j.canlet.2014.06.011</pub-id><pub-id pub-id-type="other">2-s2.0-84906064282</pub-id><pub-id pub-id-type="pmid">25011082</pub-id></element-citation></ref><ref id="B125"><label>125</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cron</surname><given-names>K. R.</given-names></name><name><surname>Zhu</surname><given-names>K.</given-names></name><name><surname>Kushwaha</surname><given-names>D. S.</given-names></name><etal></etal></person-group><article-title>Proteasome inhibitors block DNA repair and radiosensitize non-small cell lung cancer</article-title><source><italic toggle="yes">PLoS One</italic></source><year>2013</year><volume>8</volume><issue>9, article e73710</issue><pub-id pub-id-type="doi">10.1371/journal.pone.0073710</pub-id><pub-id pub-id-type="other">2-s2.0-84883543030</pub-id><pub-id pub-id-type="pmid">24040035</pub-id></element-citation></ref><ref id="B126"><label>126</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Garnett</surname><given-names>M. J.</given-names></name><name><surname>Edelman</surname><given-names>E. J.</given-names></name><name><surname>Heidorn</surname><given-names>S. J.</given-names></name><etal></etal></person-group><article-title>Systematic identification of genomic markers of drug sensitivity in cancer cells</article-title><source><italic toggle="yes">Nature</italic></source><year>2012</year><volume>483</volume><issue>7391</issue><fpage>570</fpage><lpage>575</lpage><pub-id pub-id-type="doi">10.1038/nature11005</pub-id><pub-id pub-id-type="other">2-s2.0-84859187259</pub-id><pub-id pub-id-type="pmid">22460902</pub-id></element-citation></ref><ref id="B127"><label>127</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kaufman</surname><given-names>J. M.</given-names></name><name><surname>Yamada</surname><given-names>T.</given-names></name><name><surname>Park</surname><given-names>K.</given-names></name><name><surname>Timmers</surname><given-names>C. D.</given-names></name><name><surname>Amann</surname><given-names>J. M.</given-names></name><name><surname>Carbone</surname><given-names>D. P.</given-names></name></person-group><article-title>A transcriptional signature identifies LKB1 functional status as a novel determinant of MEK sensitivity in lung adenocarcinoma</article-title><source><italic toggle="yes">Cancer Research</italic></source><year>2017</year><volume>77</volume><issue>1</issue><fpage>153</fpage><lpage>163</lpage><pub-id pub-id-type="doi">10.1158/0008-5472.can-16-1639</pub-id><pub-id pub-id-type="other">2-s2.0-85009275095</pub-id><pub-id pub-id-type="pmid">27821489</pub-id></element-citation></ref><ref id="B128"><label>128</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Skoulidis</surname><given-names>F.</given-names></name><name><surname>Byers</surname><given-names>L. A.</given-names></name><name><surname>Diao</surname><given-names>L.</given-names></name><etal></etal></person-group><article-title>Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities</article-title><source><italic toggle="yes">Cancer Discovery</italic></source><year>2015</year><volume>5</volume><issue>8</issue><fpage>860</fpage><lpage>877</lpage><pub-id pub-id-type="doi">10.1158/2159-8290.cd-14-1236</pub-id><pub-id pub-id-type="other">2-s2.0-84938794719</pub-id><pub-id pub-id-type="pmid">26069186</pub-id></element-citation></ref><ref id="B129"><label>129</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Boudeau</surname><given-names>J.</given-names></name><name><surname>Deak</surname><given-names>M.</given-names></name><name><surname>Lawlor</surname><given-names>M. A.</given-names></name><name><surname>Morrice</surname><given-names>N. A.</given-names></name><name><surname>Alessi</surname><given-names>D. R.</given-names></name></person-group><article-title>Heat-shock protein 90 and Cdc37 interact with LKB1 and regulate its stability</article-title><source><italic toggle="yes">The Biochemical Journal</italic></source><year>2003</year><volume>370</volume><issue>3</issue><fpage>849</fpage><lpage>857</lpage><pub-id pub-id-type="doi">10.1042/bj20021813</pub-id><pub-id pub-id-type="other">2-s2.0-0037444766</pub-id><pub-id pub-id-type="pmid">12489981</pub-id></element-citation></ref><ref id="B130"><label>130</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Feng</surname><given-names>F. Y.</given-names></name><name><surname>de Bono</surname><given-names>J. S.</given-names></name><name><surname>Rubin</surname><given-names>M. A.</given-names></name><name><surname>Knudsen</surname><given-names>K. E.</given-names></name></person-group><article-title>Chromatin to clinic: the molecular rationale for PARP1 inhibitor function</article-title><source><italic toggle="yes">Molecular Cell</italic></source><year>2015</year><volume>58</volume><issue>6</issue><fpage>925</fpage><lpage>934</lpage><pub-id pub-id-type="doi">10.1016/j.molcel.2015.04.016</pub-id><pub-id pub-id-type="other">2-s2.0-84937606000</pub-id><pub-id pub-id-type="pmid">26091341</pub-id></element-citation></ref><ref id="B131"><label>131</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Inge</surname><given-names>L. J.</given-names></name><name><surname>Coon</surname><given-names>K. D.</given-names></name><name><surname>Smith</surname><given-names>M. A.</given-names></name><name><surname>Bremner</surname><given-names>R. M.</given-names></name></person-group><article-title>Expression of LKB1 tumor suppressor in non-small cell lung cancer determines sensitivity to 2-deoxyglucose</article-title><source><italic toggle="yes">The Journal of Thoracic and Cardiovascular Surgery</italic></source><year>2009</year><volume>137</volume><issue>3</issue><fpage>580</fpage><lpage>586</lpage><pub-id pub-id-type="doi">10.1016/j.jtcvs.2008.11.029</pub-id><pub-id pub-id-type="other">2-s2.0-60949083610</pub-id><pub-id pub-id-type="pmid">19258070</pub-id></element-citation></ref><ref id="B132"><label>132</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kim</surname><given-names>D. W.</given-names></name><name><surname>Chung</surname><given-names>H. K.</given-names></name><name><surname>Park</surname><given-names>K. C.</given-names></name><etal></etal></person-group><article-title>Tumor suppressor LKB1 inhibits activation of signal transducer and activator of transcription 3 (STAT3) by thyroid oncogenic tyrosine kinase rearranged in transformation (RET)/papillary thyroid carcinoma (PTC)</article-title><source><italic toggle="yes">Molecular Endocrinology</italic></source><year>2007</year><volume>21</volume><issue>12</issue><fpage>3039</fpage><lpage>3049</lpage><pub-id pub-id-type="doi">10.1210/me.2007-0269</pub-id><pub-id pub-id-type="other">2-s2.0-36849022115</pub-id><pub-id pub-id-type="pmid">17761947</pub-id></element-citation></ref><ref id="B133"><label>133</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Green</surname><given-names>A. S.</given-names></name><name><surname>Chapuis</surname><given-names>N.</given-names></name><name><surname>Trovati Maciel</surname><given-names>T.</given-names></name><etal></etal></person-group><article-title>The LKB1/AMPK signaling pathway has tumor suppressor activity in acute myeloid leukemia through the repression of mTOR-dependent oncogenic mRNA translation</article-title><source><italic toggle="yes">Blood</italic></source><year>2010</year><volume>116</volume><issue>20</issue><fpage>4262</fpage><lpage>4273</lpage><pub-id pub-id-type="doi">10.1182/blood-2010-02-269837</pub-id><pub-id pub-id-type="other">2-s2.0-78549283186</pub-id><pub-id pub-id-type="pmid">20668229</pub-id></element-citation></ref><ref id="B134"><label>134</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ronan</surname><given-names>B.</given-names></name><name><surname>Flamand</surname><given-names>O.</given-names></name><name><surname>Vescovi</surname><given-names>L.</given-names></name><etal></etal></person-group><article-title>A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy</article-title><source><italic toggle="yes">Nature Chemical Biology</italic></source><year>2014</year><volume>10</volume><issue>12</issue><fpage>1013</fpage><lpage>1019</lpage><pub-id pub-id-type="doi">10.1038/nchembio.1681</pub-id><pub-id pub-id-type="other">2-s2.0-84911906578</pub-id><pub-id pub-id-type="pmid">25326666</pub-id></element-citation></ref><ref id="B135"><label>135</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bin-Umer</surname><given-names>M. A.</given-names></name><name><surname>McLaughlin</surname><given-names>J. E.</given-names></name><name><surname>Butterly</surname><given-names>M. S.</given-names></name><name><surname>McCormick</surname><given-names>S.</given-names></name><name><surname>Tumer</surname><given-names>N. E.</given-names></name></person-group><article-title>Elimination of damaged mitochondria through mitophagy reduces mitochondrial oxidative stress and increases tolerance to trichothecenes</article-title><source><italic toggle="yes">Proceedings of the National Academy of Sciences of the United States of America</italic></source><year>2014</year><volume>111</volume><issue>32</issue><fpage>11798</fpage><lpage>11803</lpage><pub-id pub-id-type="doi">10.1073/pnas.1403145111</pub-id><pub-id pub-id-type="other">2-s2.0-84905965017</pub-id><pub-id pub-id-type="pmid">25071194</pub-id></element-citation></ref><ref id="B136"><label>136</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Joo</surname><given-names>M. S.</given-names></name><name><surname>Kim</surname><given-names>W. D.</given-names></name><name><surname>Lee</surname><given-names>K. Y.</given-names></name><name><surname>Kim</surname><given-names>J. H.</given-names></name><name><surname>Koo</surname><given-names>J. H.</given-names></name><name><surname>Kim</surname><given-names>S. G.</given-names></name></person-group><article-title>AMPK facilitates nuclear accumulation of Nrf2 by phosphorylating at serine 550</article-title><source><italic toggle="yes">Molecular and Cellular Biology</italic></source><year>2016</year><volume>36</volume><issue>14</issue><fpage>1931</fpage><lpage>1942</lpage><pub-id pub-id-type="doi">10.1128/mcb.00118-16</pub-id><pub-id pub-id-type="other">2-s2.0-84977609281</pub-id><pub-id pub-id-type="pmid">27161318</pub-id></element-citation></ref><ref id="B137"><label>137</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kapuy</surname><given-names>O.</given-names></name><name><surname>Papp</surname><given-names>D.</given-names></name><name><surname>Vellai</surname><given-names>T.</given-names></name><name><surname>Banhegyi</surname><given-names>G.</given-names></name><name><surname>Korcsmaros</surname><given-names>T.</given-names></name></person-group><article-title>Systems-level feedbacks of NRF2 controlling autophagy upon oxidative stress response</article-title><source><italic toggle="yes">Antioxidants (Basel)</italic></source><year>2018</year><volume>7</volume><issue>3</issue><fpage>p. 39</fpage><pub-id pub-id-type="doi">10.3390/antiox7030039</pub-id></element-citation></ref><ref id="B138"><label>138</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Toyama</surname><given-names>E. Q.</given-names></name><name><surname>Herzig</surname><given-names>S.</given-names></name><name><surname>Courchet</surname><given-names>J.</given-names></name><etal></etal></person-group><article-title>AMP-activated protein kinase mediates mitochondrial fission in response to energy stress</article-title><source><italic toggle="yes">Science</italic></source><year>2016</year><volume>351</volume><issue>6270</issue><fpage>275</fpage><lpage>281</lpage><pub-id pub-id-type="doi">10.1126/science.aab4138</pub-id><pub-id pub-id-type="other">2-s2.0-84954318420</pub-id><pub-id pub-id-type="pmid">26816379</pub-id></element-citation></ref><ref id="B139"><label>139</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Fernandez-Marcos</surname><given-names>P. J.</given-names></name><name><surname>Auwerx</surname><given-names>J.</given-names></name></person-group><article-title>Regulation of PGC-1<italic>α</italic>, a nodal regulator of mitochondrial biogenesis</article-title><source><italic toggle="yes">The American journal of clinical nutrition</italic></source><year>2011</year><volume>93</volume><issue>4</issue><fpage>884s</fpage><lpage>890S</lpage><pub-id pub-id-type="doi">10.3945/ajcn.110.001917</pub-id><pub-id pub-id-type="other">2-s2.0-79953210362</pub-id><pub-id pub-id-type="pmid">21289221</pub-id></element-citation></ref><ref id="B140"><label>140</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kang</surname><given-names>S. W. S.</given-names></name><name><surname>Haydar</surname><given-names>G.</given-names></name><name><surname>Taniane</surname><given-names>C.</given-names></name><etal></etal></person-group><article-title>AMPK activation prevents and reverses drug-induced mitochondrial and hepatocyte injury by promoting mitochondrial fusion and function</article-title><source><italic toggle="yes">PLoS One</italic></source><year>2016</year><volume>11</volume><issue>10, article e0165638</issue><pub-id pub-id-type="doi">10.1371/journal.pone.0165638</pub-id><pub-id pub-id-type="other">2-s2.0-84993928897</pub-id><pub-id pub-id-type="pmid">27792760</pub-id></element-citation></ref></ref-list></back><floats-group><fig id="fig1" orientation="portrait" position="float"><label>Figure 1</label><caption><p>LKB1-proficient tumors display coordinated control of metabolism, DNA repair, and mitochondrial dynamics. LKB1 interacts with the pseudokinase STE20-Related Kinase Adaptor Alpha (STRAD<italic>α</italic>) and with the armadillo-repeat containing protein MO25<italic>α</italic>. Once activated, LKB1 phosphorylates AMPK, which coordinates activation of catabolic processes—such as glycolysis, Krebs cycle, pentose phosphate pathway, fatty acid oxidation, and autophagy—and inhibition of anabolic processes—such as fatty acid synthesis and mTOR pathway. This maximizes ATP production and NADPH regeneration, thus controlling energy and redox homeostasis. Moreover, AMPK promotes mitochondrial fusion and mitophagy of damaged mitochondrial portions. In the nucleus, LKB1 fosters genomic integrity through sustaining homologous recombination. Black arrows from AMPK: direct phosphorylation. Red arrows: activation/upregulation. Yellow circles: phosphate groups. Red phospholipids in membranes: peroxidised phospholipids. Red stars in the nucleus: DNA damage sites. G6P: glucose 6-phosphate; F6P: fructose 6-phosphate; F1,6BP: fructose 1,6-biphosphate; G3P: glyceraldehyde 3-phosphate; 1,3BPG: 1,3-biphosphoglycerate; 3PG: 3-phosphoglycerate; 2PG: 2-phosphoglycerate; PEP: phosphoenolpyruvate; Pyr: pyruvate; AcCoA: acetyl-coA; 6PG: 6-phosphogluconate; Ru5P: ribulose 5-phosphate; R5P: ribose 5-phosphate; GLUT: glucose transporter; GSH: reduced glutathione; GSSG: oxidized glutathione; H<sub>2</sub>O<sub>2</sub>: hydrogen peroxide; oxPPP: oxidative pentose phosphate pathway; TCA: tricarboxylic acid cycle; ETC: electron transport chain; FAO: fatty acid oxidation. The names of proteins deriving from disassembly of mTORC1 and NADPH oxidase complexes are omitted. See the text for details.</p></caption><graphic xlink:href="OMCL2019-8730816.001"></graphic></fig><fig id="fig2" orientation="portrait" position="float"><label>Figure 2</label><caption><p>LKB1 loss alters cancer cell biology. LBK1 loss and consequent lack of AMPK activation lead to mTORC1 assembly, resulting in autophagy inhibition. High metabolic requirements imposed by sustained proliferation are met through aerobic glycolysis (i.e., Warburg effect), driven by HIF-1<italic>α</italic> stabilization, which provides cancer cells with ATP and intermediates for anabolic reactions (not shown). Pyruvate is preferentially converted to lactate, which is excreted in the tumor microenvironment. Activation of ACC1 and ACC2 promotes fatty acid synthesis in the cytosol, by using citrate coming from mitochondria. NOX1 expression drives the assembly of NADPH oxidase complex, which produces ROS in the microenvironment. NOX-produced ROS enter the cell, thus inducing oxidative stress and activating NRF2 through the oxidation of KEAP1. Reduced expression of MFN1 and OPA1 and increased activity of DRP1, induced by HIF-1<italic>α</italic> activation, lead to mitochondrial fragmentation. Increased ROS levels and mitochondrial fission promote the secretion of proangiogenic factors in the microenvironment. Yellow circles: phosphate groups. Red phospholipids in membranes: peroxidised phospholipids. Red stars in the nucleus: DNA damage sites. G6P: glucose 6-phosphate; F6P: fructose 6-phosphate; F1,6BP: fructose 1,6-biphosphate; G3P: glyceraldehyde 3-phosphate; 1,3BPG: 1,3-biphosphoglycerate; 3PG: 3-phosphoglycerate; 2PG: 2-phosphoglycerate; PEP: phosphoenolpyruvate; Pyr: pyruvate; 6PG: 6-phosphogluconate; Ru5P: ribulose 5-phosphate; R5P: ribose 5-phosphate; AcCoA: acetyl-coA; MalCoA: malonyl-coA; Cit: citrate; GLUT: glucose transporter; MCT: monocarboxylate transporter; GSH: reduced glutathione; GSSG: oxidized glutathione; H<sub>2</sub>O<sub>2</sub>: hydrogen peroxide; oxPPP: oxidative pentose phosphate pathway; TCA: tricarboxylic acid cycle; FAS: fatty acid synthesis. mTORC1 targets are omitted. See the text for details.</p></caption><graphic xlink:href="OMCL2019-8730816.002"></graphic></fig><fig id="fig3" orientation="portrait" position="float"><label>Figure 3</label><caption><p>LKB1 expression regulates response to oxidative stress induced by prooxidant cytotoxic drugs. Isogenic pairs of H460 and HeLa cells (derived from NSCLC and cervical carcinoma, respectively) differing in LKB1 status and generated as described by Zulato et al. [<xref rid="B103" ref-type="bibr">103</xref>] were treated with arsenic trioxide, paclitaxel, or doxorubicin for 48 h. Viability was evaluated by the Sulphorhodamine B assay (for materials and methods, refer to [<xref rid="B103" ref-type="bibr">103</xref>]) in cells exposed to increasing concentrations of drugs. For each cell line tested, the IC<sub>50</sub> values relative to LKB1<sup>mut</sup> and LKB1<sup>wt</sup> cells are reported. Results are representative of three independent experiments performed in triplicate (<sup>§</sup><italic>P</italic> < 0.05, <sup>§§</sup><italic>P</italic> < 0.01, and <sup>§§§</sup><italic>P</italic> < 0.001 LKB1<sup>wt</sup> versus LKB1<sup>mut</sup> cells). Results of SRB assay revealed that H460 and HeLa LKB1<sup>wt</sup> variants were more resistant than their LKB1<sup>mut</sup> counterparts to the drugs tested. NE: not evaluable.</p></caption><graphic xlink:href="OMCL2019-8730816.003"></graphic></fig><table-wrap id="tab1" orientation="portrait" position="float"><label>Table 1</label><caption><p>Mitochondrial dynamics control by LKB1-AMPK.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1">Target</th><th align="center" rowspan="1" colspan="1">Role of LKB1</th><th align="center" rowspan="1" colspan="1">Biological effects</th></tr></thead><tbody><tr><td align="left" colspan="3" rowspan="1">(a) Role of LKB1/AMPK in mitochondrial fission</td></tr><tr><td align="left" rowspan="1" colspan="1">MFF (mitochondrial fission factor)</td><td align="center" rowspan="1" colspan="1">AMPK-mediated phosphorylation</td><td align="center" rowspan="1" colspan="1">MFF phosphorylation relocalizes the cytosolic GTPase Dynamin-Related Protein 1 (DRP1) to mitochondria, leading to mitochondrial fragmentation [<xref rid="B138" ref-type="bibr">138</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">ULK1 (Unc-51-Like Autophagy Activating Kinase 1)</td><td align="center" rowspan="1" colspan="1">AMPK-mediated phosphorylation</td><td align="center" rowspan="1" colspan="1">ULK1 phosphorylation initiates mitophagy of damaged mitochondria, providing cancer cells with an important loophole from therapy-induced cytotoxicity [<xref rid="B139" ref-type="bibr">139</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">PGC-1<italic>α</italic> (peroxisome proliferator-activated receptor gamma coactivator 1 alpha)</td><td align="center" rowspan="1" colspan="1">AMPK-mediated activation</td><td align="center" rowspan="1" colspan="1">Activation of PGC-1<italic>α</italic>, the master regulator of mitochondrial biogenesis, promotes the biogenesis of new mitochondria, in order to preserve mitochondrial network functionality [<xref rid="B139" ref-type="bibr">139</xref>]</td></tr><tr><td align="center" colspan="3" rowspan="1"><hr></hr></td></tr><tr><td align="left" colspan="3" rowspan="1">(b) Role of LKB1/AMPK in mitochondrial fusion</td></tr><tr><td align="left" rowspan="1" colspan="1">MFN1 (Mitofusin-1)</td><td align="center" rowspan="1" colspan="1">AMPK-mediated upregulation</td><td align="center" rowspan="1" colspan="1">MFN1 mediates outer mitochondrial membrane fusion, protecting cells from mitochondrial dysfunction following a cytotoxic injury [<xref rid="B140" ref-type="bibr">140</xref>]</td></tr><tr><td align="left" rowspan="1" colspan="1">OPA1 (Optic Atrophy 1)</td><td align="center" rowspan="1" colspan="1">AMPK-mediated upregulation</td><td align="center" rowspan="1" colspan="1">OPA1 mediates inner mitochondrial membrane fusion, protecting cells from mitochondrial dysfunction following a cytotoxic injury [<xref rid="B140" ref-type="bibr">140</xref>]</td></tr></tbody></table></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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