title: Autophagy delays sulindac sulfide-induced apoptosis in the human intestinal colon cancer cell line HT-29.
abstract: Autophagy is a major catabolic process allowing the renewal of intracellular organelles by which cells maintain their homeostasis. We have previously shown that autophagy is controlled by two transduction pathways mediated by a heterotrimeric Gi3 protein and phosphatidylinositol 3-kinase activities in the human colon cancer cell line HT-29. Here, we show that 3-methyladenine, an inhibitor of autophagy, increases the sensitivity of HT-29 cells to apoptosis induced by sulindac sulfide, a nonsteroidal anti-inflammatory drug which inhibits the cyclooxygenases. Similarly, HT-29 cells overexpressing a GTPase-deficient mutant of the G(alpha i3) protein (Q204L), which have a low rate of autophagy, were more sensitive to sulindac sulfide-induced apoptosis than parental HT-29 cells. In both cell populations we did not observe differences in the expression patterns of COX-2, Bcl-2, Bcl(XL), Bax, and Akt/PKB activity. However, the rate of cytochrome c release was higher in Q204L-overexpressing cells than in HT-29 cells. These results suggest that autophagy could retard apoptosis in colon cancer cells by sequestering mitochondrial death-promoting factors such as cytochrome c.
authors.affiliation: INSERM U504 Glycobiologie et Signalisation Cellulaire, 16, Avenue Paul-Vaillant Couturier, 94807 Villejuif Cedex, France.
authors.forename: C
authors.initials: C
authors.lastname: Bauvy
authors.forename: P
authors.initials: P
authors.lastname: Gane
authors.forename: S
authors.initials: S
authors.lastname: Arico
authors.forename: P
authors.initials: P
authors.lastname: Codogno
authors.forename: E
authors.initials: E
authors.lastname: Ogier-Denis
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology*; D001343:Autophagy / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism*; D051546:Cyclooxygenase 2; D003574:Cytochrome c Group / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D051057:Proto-Oncogene Proteins c-akt; D013467:Sulindac / Q000031:analogs & derivatives / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D003574:Cytochrome c Group; D007527:Isoenzymes; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D013467:Sulindac; C025946:3-methyladenine; C025462:sulindac sulfide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D000225:Adenine