The study, from researchers in Institute of Microbiology, Chinese Academy of Sciences, suggests a novel mechanism in 11'-deoxyverticillin A-induced tumor cell autophagy and apoptosis.
11'-deoxyverticillin A (C42), a natural product isolated from the Cordyceps-colonizing fungus Gliocladium sp.30, is a member of a class of fungal secondary metabolites known as epipolythiodioxopiperazines (ETPs). The ETPs have been previously reported to possess anti-tumor activities through promoting apoptosis or necrosis 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.
Researchers in Prof. JIANG Xuejun’s team find that C42 induces autophagosome formation, accumulation of microtubule-associated protein 1 light chain 3-II (LC3-II) and degradation of sequestosome 1 (SQSTM1/p62). 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 suppress PARP cleavage and concurrently and maximally augment the PAR formation induced by C42. Their work demonstrates 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.
The details of the work will be published in Autophagy 7(6) in June, 2011.
JIANG Xuejun, Ph.D., Professor
Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.