Following Cytochrome c Release, Autophagy Is Inhibited during Chemotherapy-Induced Apoptosis by Caspase 8–Mediated Cleavage of Beclin 1

Abstract

Autophagy is an evolutionarily conserved stress response mechanism that often occurs in apoptosis-defective cancer cells and can protect against cell death. In this study, we investigated how apoptosis and autophagy affect each other in cancer cells in response to chemotherapeutic treatment. We found that specific ablation of the proapoptotic function of cytochrome c, a key regulator of mitochondria-mediated apoptosis, enhanced autophagy following chemotherapeutic treatment. Induction of autophagy required Beclin 1, and was associated with blockage of Beclin 1 cleavage by caspase 8 at two sites. To investigate the role of Beclin 1 cleavage in the suppression of autophagy and cell survival, a caspase-resistant mutant of Beclin 1 was knocked into HCT116 colon cancer cells. Beclin 1 mutant knock-in resulted in markedly increased autophagy and improved long-term cell survival after chemotherapeutic treatment, but without affecting apoptosis and caspase activation. Furthermore, Beclin 1 mutant tumors were significantly less responsive to chemotherapeutic treatment than wild-type tumors. These results demonstrate that chemotherapy-induced apoptosis inhibits autophagy at the execution stage subsequent to cytochrome c release through caspase 8-mediated cleavage of Beclin 1. If apoptosis fails to execute, autophagy is unleashed due to lack of Beclin 1 cleavage by caspases, and can contribute to cancer cell survival and therapeutic resistance. Therefore, Beclin 1 may be a useful target for inhibiting autophagy to sensitize chemotherapy.

Caspase 1 Activation Is Protective against Hepatocyte Cell Death by Up-regulating Beclin 1 Protein and Mitochondrial Autophagy in the Setting of Redox Stress

“…5E). Beclin 1 has been shown previously to be cleaved by caspase 8 (30). To determine whether caspase 1 induces beclin 1 levels through regulating caspase 8, we assessed the activity of caspase 8 by Western blot analysis.…”

Autophagy as a mediator of chemotherapy-induced cell death in cancer

“…In order to reach clinical application, we must first better understand the factors that influence the effects of autophagy on cell death. Direct crosstalk between apoptosis and autophagy has been evidenced, and some of the mechanisms involved are aimed at reinforcing cell death [93,94]. A second issue to unravel would be to investigate whether the intensity and/or the speed of the autophagic process would determine the fate of the cell: severe and/or rapid autophagy might lead to cell death while mild and/or slow autophagy may favor cell survival.…”

Aging and uremia: Is there cellular and molecular crossover?

“…This phenomenon was subsequently shown to be due to telomere shortening [72] , but can be triggered by nontelomeric agingassociated stimuli such as DNA damage and excessive mitogenic signaling [3] . Senescent cells accumulate in aged organisms, although senescence per se does not cause aging, for both can combine via p27 [56] , p38 [57] , p53 [58] and beclin1 [59,60] . It is likely that these overlapping pathways are involved in uremia and aging induced dysfunction.…”