title: Polyphyllin I induces mitophagic and apoptotic cell death in human breast cancer cells by increasing mitochondrial PINK1 levels.
abstract: 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.
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, 3rd Military Medical University, Chongqing, China.|Department of Pharmacy, The Second Affiliated Hospital of Third Military Medical University, Chongqing, China.
authors.forename: Guo-Bing
authors.initials: GB
authors.lastname: Li
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, 3rd Military Medical University, Chongqing, China.
authors.forename: Ruo-Qiu
authors.initials: RQ
authors.lastname: Fu
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore.
authors.forename: Han-Ming
authors.initials: HM
authors.lastname: Shen
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, 3rd Military Medical University, Chongqing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, 3rd Military Medical University, Chongqing, China.
authors.forename: Xiao-Ye
authors.initials: XY
authors.lastname: Hu
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, 3rd Military Medical University, Chongqing, China.
authors.forename: Yan-Xia
authors.initials: YX
authors.lastname: Liu
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, 3rd Military Medical University, Chongqing, China.
authors.forename: Yu-Nong
authors.initials: YN
authors.lastname: Li
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, 3rd Military Medical University, Chongqing, China.
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Zhang
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, 3rd Military Medical University, Chongqing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, 3rd Military Medical University, Chongqing, China.
authors.forename: Yan-Hao
authors.initials: YH
authors.lastname: Zhang
authors.affiliation: Drug Discovery Lab, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Pharmacy, The Second Affiliated Hospital of Third Military Medical University, Chongqing, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, 3rd Military Medical University, Chongqing, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Gao
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D004144:Diosgenin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D034281:Dynamins; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D063154:Mitochondrial Dynamics / Q000187:drug effects; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D063306:Mitophagy / Q000187:drug effects*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays; D000099202:PTEN-Induced Putative Kinase
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; D004144:Diosgenin; D034281:Dynamins; D020558:GTP Phosphohydrolases; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C556217:polyphyllin I; C111567:parkin protein; C110768:DNM1L protein, human
keywords: DRP1; PINK1; mitochondrial fission; mitophagy; polyphyllin I