Colorectal cancer cells respond differentially to autophagy inhibition in vivo
Identifieur interne : 000184 ( Pmc/Curation ); précédent : 000183; suivant : 000185Colorectal cancer cells respond differentially to autophagy inhibition in vivo
Auteurs : Annie Lauzier ; Josiann Normandeau-Guimond ; Vanessa Vaillancourt-Lavigueur ; Vincent Boivin ; Martine Charbonneau ; Nathalie Rivard ; Michelle S. Scott ; Claire M. Dubois ; Steve JeanSource :
- Scientific Reports [ 2045-2322 ] ; 2019.
Abstract
Autophagy has both tumor-promoting and -suppressing effects in cancer, including colorectal cancer (CRC), with transformed cells often exhibiting high autophagic flux. In established tumors, autophagy inhibition can lead to opposite responses resulting in either tumor cell death or hyperproliferation. The functional mechanisms underlying these differences are poorly understood. The present study aimed to investigate the relationship between the autophagic capacities of CRC cells and their sensitivities to autophagy inhibition. All studied CRC cell lines showed high basal autophagic flux. However, only HCT116 and Caco-2/15 cells displayed regulated autophagic flux upon starvation. Knockdown of ATG5 (which disrupts autophagosome elongation) or RAB21 (which decreases autophagosome/lysosome fusion) had little effect on CRC cell proliferation
Url:
DOI: 10.1038/s41598-019-47659-7
PubMed: 31383875
PubMed Central: 6683171
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Annie Lauzier<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Faculté de Médecine et des Sciences de la Santé,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</nlm:aff><wicri:noCountry code="subfield">Québec J1E 4K8 Canada</wicri:noCountry></affiliation><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Department of Anatomy and Cell Biology,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</nlm:aff><wicri:noCountry code="subfield">Québec J1E 4K8 Canada</wicri:noCountry></affiliation><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Department of Anatomy and Cell Biology,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</nlm:aff><wicri:noCountry code="subfield">Québec J1E 4K8 Canada</wicri:noCountry></affiliation><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Faculté de Médecine et des Sciences de la Santé,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</nlm:aff><wicri:noCountry code="subfield">Québec J1E 4K8 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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Colorectal cancer cells respond differentially to autophagy inhibition <italic>in vivo</italic></title><author><name sortKey="Lauzier, Annie" sort="Lauzier, Annie" uniqKey="Lauzier A" first="Annie" last="Lauzier">Annie Lauzier</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Faculté de Médecine et des Sciences de la Santé,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</nlm:aff><wicri:noCountry code="subfield">Québec J1E 4K8 Canada</wicri:noCountry></affiliation><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id 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Canada</wicri:noCountry></affiliation></author><author><name sortKey="Charbonneau, Martine" sort="Charbonneau, Martine" uniqKey="Charbonneau M" first="Martine" last="Charbonneau">Martine Charbonneau</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Faculté de Médecine et des Sciences de la Santé,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</nlm:aff><wicri:noCountry code="subfield">Québec J1E 4K8 Canada</wicri:noCountry></affiliation><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Department of Anatomy and Cell Biology,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</nlm:aff><wicri:noCountry code="subfield">Québec J1E 4K8 Canada</wicri:noCountry></affiliation></author><author><name sortKey="Rivard, Nathalie" sort="Rivard, Nathalie" uniqKey="Rivard N" first="Nathalie" last="Rivard">Nathalie Rivard</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Faculté de Médecine et des Sciences de la Santé,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</nlm:aff><wicri:noCountry code="subfield">Québec J1E 4K8 Canada</wicri:noCountry></affiliation><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Department of Anatomy and Cell Biology,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</nlm:aff><wicri:noCountry code="subfield">Québec J1E 4K8 Canada</wicri:noCountry></affiliation></author><author><name sortKey="Scott, Michelle S" sort="Scott, Michelle S" uniqKey="Scott M" first="Michelle S." last="Scott">Michelle S. Scott</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Faculté de Médecine et des Sciences de la Santé,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</nlm:aff><wicri:noCountry code="subfield">Québec J1E 4K8 Canada</wicri:noCountry></affiliation><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Department of Biochemistry,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</nlm:aff><wicri:noCountry code="subfield">Québec J1E 4K8 Canada</wicri:noCountry></affiliation></author><author><name sortKey="Dubois, Claire M" sort="Dubois, Claire M" uniqKey="Dubois C" first="Claire M." last="Dubois">Claire M. Dubois</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Faculté de Médecine et des Sciences de la Santé,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</nlm:aff><wicri:noCountry code="subfield">Québec J1E 4K8 Canada</wicri:noCountry></affiliation><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Department of Anatomy and Cell Biology,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</nlm:aff><wicri:noCountry code="subfield">Québec J1E 4K8 Canada</wicri:noCountry></affiliation></author><author><name sortKey="Jean, Steve" sort="Jean, Steve" uniqKey="Jean S" first="Steve" last="Jean">Steve Jean</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Faculté de Médecine et des Sciences de la Santé,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</nlm:aff><wicri:noCountry code="subfield">Québec J1E 4K8 Canada</wicri:noCountry></affiliation><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Department of Anatomy and Cell Biology,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</nlm:aff><wicri:noCountry code="subfield">Québec J1E 4K8 Canada</wicri:noCountry></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31383875</idno><idno type="pmc">6683171</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683171</idno><idno type="RBID">PMC:6683171</idno><idno type="doi">10.1038/s41598-019-47659-7</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000184</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000184</idno><idno type="wicri:Area/Pmc/Curation">000184</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000184</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Colorectal cancer cells respond differentially to autophagy inhibition <italic>in vivo</italic></title><author><name sortKey="Lauzier, Annie" sort="Lauzier, Annie" uniqKey="Lauzier A" first="Annie" last="Lauzier">Annie Lauzier</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Faculté de Médecine et des Sciences de la Santé,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</nlm:aff><wicri:noCountry code="subfield">Québec J1E 4K8 Canada</wicri:noCountry></affiliation><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Department of Anatomy and Cell Biology,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</nlm:aff><wicri:noCountry code="subfield">Québec J1E 4K8 Canada</wicri:noCountry></affiliation></author><author><name sortKey="Normandeau Guimond, Josiann" sort="Normandeau Guimond, Josiann" uniqKey="Normandeau Guimond J" first="Josiann" last="Normandeau-Guimond">Josiann Normandeau-Guimond</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Faculté de Médecine et des Sciences de la Santé,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</nlm:aff><wicri:noCountry code="subfield">Québec J1E 4K8 Canada</wicri:noCountry></affiliation><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Department of Anatomy and Cell Biology,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</nlm:aff><wicri:noCountry code="subfield">Québec J1E 4K8 Canada</wicri:noCountry></affiliation></author><author><name sortKey="Vaillancourt Lavigueur, Vanessa" sort="Vaillancourt Lavigueur, Vanessa" uniqKey="Vaillancourt Lavigueur V" first="Vanessa" last="Vaillancourt-Lavigueur">Vanessa Vaillancourt-Lavigueur</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Faculté de Médecine et des Sciences de la Santé,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</nlm:aff><wicri:noCountry code="subfield">Québec J1E 4K8 Canada</wicri:noCountry></affiliation><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Department of Anatomy and Cell Biology,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</nlm:aff><wicri:noCountry code="subfield">Québec J1E 4K8 Canada</wicri:noCountry></affiliation></author><author><name sortKey="Boivin, Vincent" sort="Boivin, Vincent" uniqKey="Boivin V" first="Vincent" last="Boivin">Vincent Boivin</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Faculté de Médecine et des Sciences de la Santé,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</nlm:aff><wicri:noCountry code="subfield">Québec J1E 4K8 Canada</wicri:noCountry></affiliation><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Department of Biochemistry,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</nlm:aff><wicri:noCountry code="subfield">Québec J1E 4K8 Canada</wicri:noCountry></affiliation></author><author><name sortKey="Charbonneau, Martine" sort="Charbonneau, Martine" uniqKey="Charbonneau M" first="Martine" last="Charbonneau">Martine Charbonneau</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Faculté de Médecine et des Sciences de la Santé,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</nlm:aff><wicri:noCountry code="subfield">Québec J1E 4K8 Canada</wicri:noCountry></affiliation><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Department of Anatomy and Cell Biology,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</nlm:aff><wicri:noCountry code="subfield">Québec J1E 4K8 Canada</wicri:noCountry></affiliation></author><author><name sortKey="Rivard, Nathalie" sort="Rivard, Nathalie" uniqKey="Rivard N" first="Nathalie" last="Rivard">Nathalie Rivard</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Faculté de Médecine et des Sciences de la Santé,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</nlm:aff><wicri:noCountry code="subfield">Québec J1E 4K8 Canada</wicri:noCountry></affiliation><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Department of Anatomy and Cell Biology,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</nlm:aff><wicri:noCountry code="subfield">Québec J1E 4K8 Canada</wicri:noCountry></affiliation></author><author><name sortKey="Scott, Michelle S" sort="Scott, Michelle S" uniqKey="Scott M" first="Michelle S." last="Scott">Michelle S. Scott</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Faculté de Médecine et des Sciences de la Santé,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</nlm:aff><wicri:noCountry code="subfield">Québec J1E 4K8 Canada</wicri:noCountry></affiliation><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Department of Biochemistry,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</nlm:aff><wicri:noCountry code="subfield">Québec J1E 4K8 Canada</wicri:noCountry></affiliation></author><author><name sortKey="Dubois, Claire M" sort="Dubois, Claire M" uniqKey="Dubois C" first="Claire M." last="Dubois">Claire M. Dubois</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Faculté de Médecine et des Sciences de la Santé,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</nlm:aff><wicri:noCountry code="subfield">Québec J1E 4K8 Canada</wicri:noCountry></affiliation><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Department of Anatomy and Cell Biology,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</nlm:aff><wicri:noCountry code="subfield">Québec J1E 4K8 Canada</wicri:noCountry></affiliation></author><author><name sortKey="Jean, Steve" sort="Jean, Steve" uniqKey="Jean S" first="Steve" last="Jean">Steve Jean</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Faculté de Médecine et des Sciences de la Santé,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</nlm:aff><wicri:noCountry code="subfield">Québec J1E 4K8 Canada</wicri:noCountry></affiliation><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Department of Anatomy and Cell Biology,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</nlm:aff><wicri:noCountry code="subfield">Québec J1E 4K8 Canada</wicri:noCountry></affiliation></author></analytic><series><title level="j">Scientific Reports</title><idno type="eISSN">2045-2322</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 id="Par1">Autophagy has both tumor-promoting and -suppressing effects in cancer, including colorectal cancer (CRC), with transformed cells often exhibiting high autophagic flux. In established tumors, autophagy inhibition can lead to opposite responses resulting in either tumor cell death or hyperproliferation. The functional mechanisms underlying these differences are poorly understood. The present study aimed to investigate the relationship between the autophagic capacities of CRC cells and their sensitivities to autophagy inhibition. All studied CRC cell lines showed high basal autophagic flux. However, only HCT116 and Caco-2/15 cells displayed regulated autophagic flux upon starvation. Knockdown of ATG5 (which disrupts autophagosome elongation) or RAB21 (which decreases autophagosome/lysosome fusion) had little effect on CRC cell proliferation <italic>in vitro</italic>. Nonetheless, inhibition of autophagy <italic>in vivo</italic> had a substantial cell line-dependent impact on tumor growth, with some cells displaying decreased (HCT116 and Caco-2/15) or increased (SW480 and LoVo) proliferation. RNA sequencing and Western blot analyses in hyperproliferative SW480 tumors revealed that the mTORC2 and AKT pathways were hyperactivated following autophagy impairment. Inhibition of either mTOR or AKT activities rescued the observed hyperproliferation in autophagy-inhibited SW480 and reduced tumor growth. These results highlight that autophagy inhibition can lead, in specific cellular contexts, to compensatory mechanisms promoting tumor growth.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Shintani, T" uniqKey="Shintani T">T Shintani</name></author><author><name sortKey="Klionsky, Dj" uniqKey="Klionsky D">DJ Klionsky</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yang, Z" uniqKey="Yang Z">Z Yang</name></author><author><name sortKey="Klionsky, Dj" uniqKey="Klionsky D">DJ Klionsky</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ravikumar, B" uniqKey="Ravikumar B">B Ravikumar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Levine, B" uniqKey="Levine B">B Levine</name></author><author><name sortKey="Kroemer, G" uniqKey="Kroemer G">G Kroemer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Galluzzi, L" uniqKey="Galluzzi L">L Galluzzi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Levine, B" uniqKey="Levine B">B Levine</name></author><author><name sortKey="Kroemer, G" uniqKey="Kroemer G">G Kroemer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kimmelman, Ac" uniqKey="Kimmelman A">AC Kimmelman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, L" uniqKey="Wang L">L Wang</name></author><author><name sortKey="Wang, Y" uniqKey="Wang Y">Y Wang</name></author><author><name sortKey="Lu, Y" uniqKey="Lu Y">Y Lu</name></author><author><name sortKey="Zhang, Q" uniqKey="Zhang Q">Q Zhang</name></author><author><name sortKey="Qu, X" uniqKey="Qu X">X Qu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mari O, G" uniqKey="Mari O G">G Mariño</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rao, S" uniqKey="Rao S">S Rao</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Mulcahy Levy, Jm" uniqKey="Mulcahy Levy J">JM Mulcahy-levy</name></author><author><name sortKey="Towers, Cg" uniqKey="Towers C">CG Towers</name></author><author><name sortKey="Thorburn, A" uniqKey="Thorburn A">A Thorburn</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Guo, Jy" uniqKey="Guo J">JY Guo</name></author><author><name sortKey="Xia, B" uniqKey="Xia B">B Xia</name></author><author><name sortKey="White, E" uniqKey="White E">E White</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Guo, Jy" uniqKey="Guo J">JY Guo</name></author><author><name sortKey="White, E" uniqKey="White E">E White</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yang, S" uniqKey="Yang S">S Yang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Guo, Jy" uniqKey="Guo J">JY Guo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Eng, Ch" uniqKey="Eng C">CH Eng</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hart, Traver" uniqKey="Hart T">Traver Hart</name></author><author><name sortKey="Chandrashekhar, Megha" uniqKey="Chandrashekhar M">Megha Chandrashekhar</name></author><author><name sortKey="Aregger, Michael" uniqKey="Aregger M">Michael Aregger</name></author><author><name sortKey="Steinhart, Zachary" uniqKey="Steinhart Z">Zachary Steinhart</name></author><author><name sortKey="Brown, Kevin R" uniqKey="Brown K">Kevin R. Brown</name></author><author><name sortKey="Macleod, Graham" uniqKey="Macleod G">Graham MacLeod</name></author><author><name sortKey="Mis, Monika" uniqKey="Mis M">Monika Mis</name></author><author><name sortKey="Zimmermann, Michal" uniqKey="Zimmermann M">Michal Zimmermann</name></author><author><name sortKey="Fradet Turcotte, Amelie" uniqKey="Fradet Turcotte A">Amelie Fradet-Turcotte</name></author><author><name sortKey="Sun, Song" uniqKey="Sun S">Song Sun</name></author><author><name sortKey="Mero, Patricia" uniqKey="Mero P">Patricia Mero</name></author><author><name sortKey="Dirks, Peter" uniqKey="Dirks P">Peter Dirks</name></author><author><name sortKey="Sidhu, Sachdev" uniqKey="Sidhu S">Sachdev Sidhu</name></author><author><name sortKey="Roth, Frederick P" uniqKey="Roth F">Frederick P. Roth</name></author><author><name sortKey="Rissland, Olivia S" uniqKey="Rissland O">Olivia S. 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Kinsey</name></author><author><name sortKey="Camolotto, Soledad A" uniqKey="Camolotto S">Soledad A. Camolotto</name></author><author><name sortKey="Boespflug, Amelie M" uniqKey="Boespflug A">Amelie M. Boespflug</name></author><author><name sortKey="Guillen, Katrin P" uniqKey="Guillen K">Katrin P. Guillen</name></author><author><name sortKey="Foth, Mona" uniqKey="Foth M">Mona Foth</name></author><author><name sortKey="Truong, Amanda" uniqKey="Truong A">Amanda Truong</name></author><author><name sortKey="Schuman, Sophia S" uniqKey="Schuman S">Sophia S. Schuman</name></author><author><name sortKey="Shea, Jill E" uniqKey="Shea J">Jill E. Shea</name></author><author><name sortKey="Seipp, Michael T" uniqKey="Seipp M">Michael T. Seipp</name></author><author><name sortKey="Yap, Jeffrey T" uniqKey="Yap J">Jeffrey T. Yap</name></author><author><name sortKey="Burrell, Lance D" uniqKey="Burrell L">Lance D. Burrell</name></author><author><name sortKey="Lum, David H" uniqKey="Lum D">David H. 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article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Sci Rep</journal-id><journal-id journal-id-type="iso-abbrev">Sci Rep</journal-id><journal-title-group><journal-title>Scientific Reports</journal-title></journal-title-group><issn pub-type="epub">2045-2322</issn><publisher><publisher-name>Nature Publishing Group UK</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31383875</article-id><article-id pub-id-type="pmc">6683171</article-id><article-id pub-id-type="publisher-id">47659</article-id><article-id pub-id-type="doi">10.1038/s41598-019-47659-7</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Colorectal cancer cells respond differentially to autophagy inhibition <italic>in vivo</italic></article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Lauzier</surname><given-names>Annie</given-names></name><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Normandeau-Guimond</surname><given-names>Josiann</given-names></name><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Vaillancourt-Lavigueur</surname><given-names>Vanessa</given-names></name><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Boivin</surname><given-names>Vincent</given-names></name><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Charbonneau</surname><given-names>Martine</given-names></name><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Rivard</surname><given-names>Nathalie</given-names></name><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Scott</surname><given-names>Michelle S.</given-names></name><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Dubois</surname><given-names>Claire M.</given-names></name><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0001-6881-5781</contrib-id><name><surname>Jean</surname><given-names>Steve</given-names></name><address><email>steve.jean@usherbrooke.ca</email></address><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff2">2</xref></contrib><aff id="Aff1"><label>1</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Faculté de Médecine et des Sciences de la Santé,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</aff><aff id="Aff2"><label>2</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Department of Anatomy and Cell Biology,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</aff><aff id="Aff3"><label>3</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9064 6198</institution-id><institution-id institution-id-type="GRID">grid.86715.3d</institution-id><institution>Department of Biochemistry,</institution><institution>Université de Sherbrooke,</institution></institution-wrap>3201, Rue Jean Mignault, Sherbrooke, Québec J1E 4K8 Canada</aff></contrib-group><pub-date pub-type="epub"><day>5</day><month>8</month><year>2019</year></pub-date><pub-date pub-type="pmc-release"><day>5</day><month>8</month><year>2019</year></pub-date><pub-date pub-type="collection"><year>2019</year></pub-date><volume>9</volume><elocation-id>11316</elocation-id><history><date date-type="received"><day>7</day><month>5</month><year>2019</year></date><date date-type="accepted"><day>19</day><month>7</month><year>2019</year></date></history><permissions><copyright-statement>© The Author(s) 2019</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold> This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>.</license-p></license></permissions><abstract id="Abs1"><p id="Par1">Autophagy has both tumor-promoting and -suppressing effects in cancer, including colorectal cancer (CRC), with transformed cells often exhibiting high autophagic flux. In established tumors, autophagy inhibition can lead to opposite responses resulting in either tumor cell death or hyperproliferation. The functional mechanisms underlying these differences are poorly understood. The present study aimed to investigate the relationship between the autophagic capacities of CRC cells and their sensitivities to autophagy inhibition. All studied CRC cell lines showed high basal autophagic flux. However, only HCT116 and Caco-2/15 cells displayed regulated autophagic flux upon starvation. Knockdown of ATG5 (which disrupts autophagosome elongation) or RAB21 (which decreases autophagosome/lysosome fusion) had little effect on CRC cell proliferation <italic>in vitro</italic>. Nonetheless, inhibition of autophagy <italic>in vivo</italic> had a substantial cell line-dependent impact on tumor growth, with some cells displaying decreased (HCT116 and Caco-2/15) or increased (SW480 and LoVo) proliferation. RNA sequencing and Western blot analyses in hyperproliferative SW480 tumors revealed that the mTORC2 and AKT pathways were hyperactivated following autophagy impairment. Inhibition of either mTOR or AKT activities rescued the observed hyperproliferation in autophagy-inhibited SW480 and reduced tumor growth. These results highlight that autophagy inhibition can lead, in specific cellular contexts, to compensatory mechanisms promoting tumor growth.</p></abstract><kwd-group kwd-group-type="npg-subject"><title>Subject terms</title><kwd>Colon cancer</kwd><kwd>Macroautophagy</kwd></kwd-group><funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">https://doi.org/10.13039/501100000024</institution-id><institution>Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)</institution></institution-wrap></funding-source><award-id>142305</award-id><principal-award-recipient><name><surname>Jean</surname><given-names>Steve</given-names></name></principal-award-recipient></award-group></funding-group><funding-group><award-group><funding-source><institution>Centre d’Excellence en Recherche en Inflammation et Oncologie Digestive de l’Université de Sherbrooke</institution></funding-source></award-group></funding-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2019</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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