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Polyphyllin I induces mitophagic and apoptotic cell death in human breast cancer cells by increasing mitochondrial PINK1 levels

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 Ser63...

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Autores principales: Li, Guo-Bing, Fu, Ruo-Qiu, Shen, Han-Ming, Zhou, Jing, Hu, Xiao-Ye, Liu, Yan-Xia, Li, Yu-Nong, Zhang, Hong-Wei, Liu, Xin, Zhang, Yan-Hao, Huang, Cheng, Zhang, Rong, Gao, Ning
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354664/
https://www.ncbi.nlm.nih.gov/pubmed/28060722
http://dx.doi.org/10.18632/oncotarget.14413
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author Li, Guo-Bing
Fu, Ruo-Qiu
Shen, Han-Ming
Zhou, Jing
Hu, Xiao-Ye
Liu, Yan-Xia
Li, Yu-Nong
Zhang, Hong-Wei
Liu, Xin
Zhang, Yan-Hao
Huang, Cheng
Zhang, Rong
Gao, Ning
author_facet Li, Guo-Bing
Fu, Ruo-Qiu
Shen, Han-Ming
Zhou, Jing
Hu, Xiao-Ye
Liu, Yan-Xia
Li, Yu-Nong
Zhang, Hong-Wei
Liu, Xin
Zhang, Yan-Hao
Huang, Cheng
Zhang, Rong
Gao, Ning
author_sort Li, Guo-Bing
collection PubMed
description 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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spelling pubmed-53546642017-04-14 Polyphyllin I induces mitophagic and apoptotic cell death in human breast cancer cells by increasing mitochondrial PINK1 levels Li, Guo-Bing Fu, Ruo-Qiu Shen, Han-Ming Zhou, Jing Hu, Xiao-Ye Liu, Yan-Xia Li, Yu-Nong Zhang, Hong-Wei Liu, Xin Zhang, Yan-Hao Huang, Cheng Zhang, Rong Gao, Ning Oncotarget Research Paper 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. Impact Journals LLC 2017-01-02 /pmc/articles/PMC5354664/ /pubmed/28060722 http://dx.doi.org/10.18632/oncotarget.14413 Text en Copyright: © 2017 Li et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Li, Guo-Bing
Fu, Ruo-Qiu
Shen, Han-Ming
Zhou, Jing
Hu, Xiao-Ye
Liu, Yan-Xia
Li, Yu-Nong
Zhang, Hong-Wei
Liu, Xin
Zhang, Yan-Hao
Huang, Cheng
Zhang, Rong
Gao, Ning
Polyphyllin I induces mitophagic and apoptotic cell death in human breast cancer cells by increasing mitochondrial PINK1 levels
title Polyphyllin I induces mitophagic and apoptotic cell death in human breast cancer cells by increasing mitochondrial PINK1 levels
title_full Polyphyllin I induces mitophagic and apoptotic cell death in human breast cancer cells by increasing mitochondrial PINK1 levels
title_fullStr Polyphyllin I induces mitophagic and apoptotic cell death in human breast cancer cells by increasing mitochondrial PINK1 levels
title_full_unstemmed Polyphyllin I induces mitophagic and apoptotic cell death in human breast cancer cells by increasing mitochondrial PINK1 levels
title_short Polyphyllin I induces mitophagic and apoptotic cell death in human breast cancer cells by increasing mitochondrial PINK1 levels
title_sort polyphyllin i induces mitophagic and apoptotic cell death in human breast cancer cells by increasing mitochondrial pink1 levels
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354664/
https://www.ncbi.nlm.nih.gov/pubmed/28060722
http://dx.doi.org/10.18632/oncotarget.14413
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