Hypoxia-induced downregulation of autophagy mediator Beclin 1 reduces the susceptibility of malignant intestinal epithelial cells to hypoxia-dependent apoptosis.
Disruption of tumor blood supply causes tumor hypoxia. Hypoxia can induce cell death, but cancer cells that remain viable in the absence of oxygen often possess an increased survival potential, and tumors formed by these cells tend to grow particularly aggressively. Thus, developing approaches aimed at increasing the susceptibility of malignant cells to hypoxia-induced death represents a potentially important avenue for cancer treatment. Molecular mechanisms that control the survival of cancer cells under hypoxia are not well understood. In an effort to understand them we found that hypoxia downregulates Beclin 1, a mediator of autophagy, in malignant intestinal epithelial cells. The reversal of this downregulation promoted autophagosome accumulation, enhanced the activation of a pro-apoptotic protease caspase-9 and subsequent caspase-9-dependent activation of two other pro-apoptotic proteases caspases 3 and 7 in these cells. Furthermore, the reversal of hypoxia-induced downregulation of Beclin 1-stimulated caspase-9-dependent apoptosis of the indicated cells under hypoxia. Interestingly, we found that Beclin 1-dependent caspase-9 activation in hypoxic cells was not associated with an increased release of cytochrome c from the mitochondria to the cytoplasm (such release represents a frequently occurring mechanism for caspase-9 activation). We also observed that Beclin 1-dependent apoptosis of hypoxic malignant cells was independent of FADD, a mediator of death receptor signaling. We conclude that hypoxia triggers a feedback mechanism that delays apoptosis of oxygen-deprived malignant intestinal epithelial cells and is driven by hypoxia-induced Beclin 1 downregulation. Thus, approaches aimed at the disruption of this mechanism can be expected to enhance the susceptibility of such cells to hypoxia-induced apoptosis.
Yoo
Byong Hoon
BH
Department of Pediatrics, Atlantic Research Centre, Dalhousie University, Halifax, NS, Canada.
Wu
Xue
X
Derouet
Mathieu
M
Haniff
Mehnaaz
M
Eskelinen
Eeva-Liisa
EL
Rosen
Kirill
K
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy / Q000187:drug effects; D000071186:Beclin-1; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D000074923:High-Temperature Requirement A Serine Peptidase 2; D007422:Intestines / Q000473:pathology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000077146:Irinotecan; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D024101:Mitochondrial Proteins / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D012697:Serine Endopeptidases / Q000378:metabolism; D014617:Vacuoles / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D002166:Camptothecin; D020169:Caspases; D045304:Cytochromes c; D053200:Fas-Associated Death Domain Protein; D000074923:High-Temperature Requirement A Serine Peptidase 2; D047908:Intracellular Signaling Peptides and Proteins; D000077146:Irinotecan; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D010100:Oxygen; D012697:Serine Endopeptidases; C512829:Becn1 protein, rat; C412403:DIABLO protein, human; C526109:Anxa3 protein, rat