Macroautophagy (hereafter referred to as autophagy) is a lysosomal degradation process whereby cellular components, such as damaged organelles, are enclosed in double-membrane structures called autophagosomes and delivered to lysosomes for degradation and recycling. Autophagy is known to be essential for cancer pathogenesis and progression through its intimate crosstalk with programed cell death machinery, apoptosis. However, the role of autophagy in apoptosis pathway remains highly controversial and context-dependent, which makes developing autophagy-targeted anti-cancer treatments hard to achieve. We have previously reported that autophagosomal membranes can serve as a platform for caspase-8 activation through the assembly of an intracellular Death-Inducing Signaling Complex (iDISC). In the present study, we demonstrate that inhibition of phagophore closure by depleting Atg2A/B stabilizes iDISCs and induces caspase-8-initiated apoptosis in acute myeloid leukemia (AML) cells. We found that knockout of Atg2A/B, but not Atg7, promotes the oligomerization of caspase-8 on Atg16L- and LC3-positive phagophore membranes upon nutrient starvation. Starvation-induced capase-8 activation and apoptosis induction in Atg2A/B-deficient cells were strongly suppressed by the inhibition of caspase-8. These results suggest that autophagy inhibition at the phagophore closure step can shift cytoprotective autophagy to a pro-death mechanism and thus may be a promising strategy to enhance the efficacy of anticancer therapy.
Citation Format: Zhenyuan Tang, Yoshinori Takahashi, Hong-Gang Wang. Inhibition of autophagosome closure promotes iDISC-mediated apoptosis in AML cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3527.