title: PARP and RIP 1 are required for autophagy induced by 11'-deoxyverticillin A, which precedes caspase-dependent apoptosis.
abstract: The epipolythiodioxopiperazines (ETPs) are fungal secondary metabolites proven to trigger both apoptotic and necrotic cell death of tumor cells. However, the underlying mechanism of their regulatory role in macroautophagy and the interplay between autophagy and apoptosis initiated by the ETPs, remain unexplored. In the current work, we found that 11'-deoxyverticillin A (C42), a member of the ETPs, induces autophagosome formation, accumulation of microtubule-associated protein 1 light chain 3-II (LC3-II ) and degradation of sequestosome 1 (SQSTM1/p62). In addition, the LC3-II accrual and p62 degradation occur prior to caspase activation and coincide with PARP activation. Inhibition of autophagy by either chemical inhibitors or by RNA interference single knockdown of essential autophagic genes partially reduces the cell death and the cleavage of both caspase 3 and PARP. Necrostatin-1, a specific inhibitor of necroptosis, inhibits both the augmentation of LC3-II and the cleavage of caspase 3, which was confirmed by depletion of receptor-interacting protein 1 (RIP-1), a crucial necrostatin-1-targeted adaptor kinase mediating cell death and survival. Moreover, inhibition of PARP by either chemical inhibitors or RNA interference provides obvious protection for cell viability and suppresses the LC3-II accretion caused by C42 treatment. Interestingly, double silencing of LC3 and p62 completely suppressed PARP cleavage and concurrently and maximally augmented the PAR formation induced by C42. Collectively, we have demonstrated that C42 enhances the cellular autophagic process, which requires both PARP and RIP-1 participation, preceding and possibly augmenting, the caspase-dependent apoptotic cell death.
authors: National Research Center of Urological Cancer, Institute of Urology, Peking University First Hospital, Beijing, China.
authors: Nan
authors: N
authors: Zhang
authors: Yali
authors: Y
authors: Chen
authors: Ruixuan
authors: R
authors: Jiang
authors: Erwei
authors: E
authors: Li
authors: Xiuling
authors: X
authors: Chen
authors: Zhijun
authors: Z
authors: Xi
authors: Yinglu
authors: Y
authors: Guo
authors: Xingzhong
authors: X
authors: Liu
authors: Yuguang
authors: Y
authors: Zhou
authors: Yongsheng
authors: Y
authors: Che
authors: Xuejun
authors: X
authors: Jiang
mesh_terms: D017209:Apoptosis; D001343:Autophagy; D053148:Caspase 3 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D003106:Colon / Q000166:cytology; D004220:Disulfides / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008954:Models, Biological; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism*; D010588:Phagosomes / Q000378:metabolism; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000378:metabolism*
chemical_list: C119724:AGFG1 protein, human; D004220:Disulfides; D028861:Nuclear Pore Complex Proteins; D010879:Piperazines; D016601:RNA-Binding Proteins; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D020169:Caspases; C540279:11,11'-dideoxyverticillin A