LKB1/AMPK Pathway and Drug Response in Cancer: A Therapeutic Perspective
Identifieur interne : 000A91 ( Pmc/Curation ); précédent : 000A90; suivant : 000A92LKB1/AMPK Pathway and Drug Response in Cancer: A Therapeutic Perspective
Auteurs : Francesco Ciccarese [Italie] ; Elisabetta Zulato [Italie] ; Stefano Indraccolo [Italie]Source :
- 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
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<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 wicri:level="1"><nlm:aff id="I1">Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Istituto Oncologico Veneto IOV-IRCCS, Padova</wicri:regionArea></affiliation></author><author><name sortKey="Zulato, Elisabetta" sort="Zulato, Elisabetta" uniqKey="Zulato E" first="Elisabetta" last="Zulato">Elisabetta Zulato</name><affiliation wicri:level="1"><nlm:aff id="I1">Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Istituto Oncologico Veneto IOV-IRCCS, Padova</wicri:regionArea></affiliation></author><author><name sortKey="Indraccolo, Stefano" sort="Indraccolo, Stefano" uniqKey="Indraccolo S" first="Stefano" last="Indraccolo">Stefano Indraccolo</name><affiliation wicri:level="1"><nlm:aff id="I1">Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Istituto Oncologico Veneto IOV-IRCCS, Padova</wicri:regionArea></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><idno type="wicri:Area/Pmc/Curation">000A91</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">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 wicri:level="1"><nlm:aff id="I1">Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Istituto Oncologico Veneto IOV-IRCCS, Padova</wicri:regionArea></affiliation></author><author><name sortKey="Zulato, Elisabetta" sort="Zulato, Elisabetta" uniqKey="Zulato E" first="Elisabetta" last="Zulato">Elisabetta Zulato</name><affiliation wicri:level="1"><nlm:aff id="I1">Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Istituto Oncologico Veneto IOV-IRCCS, Padova</wicri:regionArea></affiliation></author><author><name sortKey="Indraccolo, Stefano" sort="Indraccolo, Stefano" uniqKey="Indraccolo S" first="Stefano" last="Indraccolo">Stefano Indraccolo</name><affiliation wicri:level="1"><nlm:aff id="I1">Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Istituto Oncologico Veneto IOV-IRCCS, Padova</wicri:regionArea></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. 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<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><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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