Polyphyllin I induces mitophagic and apoptotic cell death in human breast cancer cells by increasing mitochondrial PINK1 levels
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Guo-Bing Li1,2,*, Ruo-Qiu Fu1,*, Han-Ming Shen3, Jing Zhou1, Xiao-Ye Hu1, Yan-Xia Liu1, Yu-Nong Li1, Hong-Wei Zhang1, Xin Liu1, Yan-Hao Zhang1, Cheng Huang4, Rong Zhang2, Ning Gao1
1Department of Pharmacognosy, College of Pharmacy, 3rd Military Medical University, Chongqing, China
2Department of Pharmacy, The Second Affiliated Hospital of Third Military Medical University, Chongqing, China
3Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore
4Drug Discovery Lab, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
*These authors have contributed equally to this work
Ning Gao, email: [email protected]
Rong Zhang, email: [email protected]
Keywords: polyphyllin I, DRP1, mitochondrial fission, mitophagy, PINK1
Received: May 17, 2016 Accepted: December 12, 2016 Published: January 02, 2017
The molecular mechanisms underlying the anti-breast cancer effects of polyphyllin I, a natural compound extracted from Paris polyphylla rhizomes, are not fully understood. In the present study, we found that polyphyllin I induces mitochondrial translocation of DRP1 by dephosphorylating DRP1 at Ser637, leading to mitochondrial fission, cytochrome c release from mitochondria into the cytosol and, ultimately apoptosis. Polyphyllin I also increased the stabilization of full-length PINK1 at the mitochondrial surface, leading to the recruitment of PARK2, P62, ubiquitin, and LC3B-II to mitochondria and culminating in mitophagy. PINK1 knockdown markedly suppressed polyphyllin I-induced mitophagy and enhanced polyphyllin I-induced, DRP1-dependent mitochondrial fission and apoptosis. Furthermore, suppression of DRP1 by mdivi-1 or shRNA inhibited PINK1 knockdown/polyphyllin I-induced mitochondrial fragmentation and apoptosis, suggesting that PINK1 depletion leads to excessive fission and, subsequently, mitochondrial fragmentation. An in vivo study confirmed that polyphyllin I greatly inhibited tumor growth and induced apoptosis in MDA-MB-231 xenografts, and these effects were enhanced by PINK1 knockdown. These data describe the mechanism by which PINK1 contributes to polyphyllin I-induced mitophagy and apoptosis and suggest that polyphyllin I may be an effective drug for breast cancer treatment.
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