Depletion of PINK1 sensitizes breast cancer cells to polyphyllin Ⅰ via mitophagy suppression and DRP1-mediated mitochondrial fission  

作　　者：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 

机构地区：[1]College of Pharmacy,3rd Military Medical University [2]Department of Pharmacy,The Second Affiliated Hospital of Third Military Medical University [3]Department of Physiology,Yong Loo Lin School of Medicine,National University of Singapore [4]Drug Discovery Lab,School of Pharmacy,Shanghai University of Traditional Chinese Medicine

出　　处：《中国药理学与毒理学杂志》2016年第10期1074-1074,共1页Chinese Journal of Pharmacology and Toxicology

基　　金：The project supported by National Natural Science Foundation of China(81402970,81402202,81402013,81202869)

摘　　要：OBJECTIVE To elucidate the molecular mechanism and the anti-breast cancer effect of polyphyllinⅠ,which is a natural compound extracted from Rhizoma of Paris polyphyllin.METHODS Human breast cancer cells were treated with polyphyllinⅠ,after which DRP1-dependent mitochondrial fission and apoptosis,mitophagy and PINK1/PARK2 pathway were evaluated.A genetic approach was employed to determine how knockdown of PINK1 with sh RNA regulates polyphyllinⅠ-induced mitophagy and apoptosis.The inhibitory effect of polyphyllinⅠon tumor growth in a breast cancer cell xenograft mouse model was also examined.RESULTS PolyphyllinⅠenhanced the stabilization of full-length PINK1at the mitochondrial surface,leading to PARK2 recruitment to mitochondria,and culminating in mitophagy.PolyphyllinⅠalso induced dephosphorylation of DRP1 at Ser637 and mitochondrial translocation of DRP1,leading to mitochondrial fission and apoptosis.Knockdown of PINK1 evidently suppressed mitophagy stimulated by polyphyllinⅠ,and markedly enhanced DRP1-dependent mitochondrial fission and apoptosis induced by polyphyl inⅠ.Furthermore,suppression of DRP1 by mdivi-1 or sh RNA inhibits PINK1 knockdown-mediated mitochondrial fragmentation and apoptosis in response to polyphyllinⅠtreatment,suggesting that depletion of PINK1 lead to mitochondrial fragmentation due to excessive fission.Our in vivo study also showed that knockdown of PINK1potentiated polyphyllinⅠ-mediated inhibition of tumor growth in a breast cancer cell xenograft mouse model.CONCLUSION Our study provides a mechanism to support the role of PINK1 in the regulation of polyphyl inⅠ-induced mitophagy and apoptosis,and suggest polyphylinⅠas a potential drug for treatment of breast cancer.OBJECTIVE To elucidate the molecular mechanism and the anti-breast cancer effect of polyphyllinⅠ,which is a natural compound extracted from Rhizoma of Paris polyphyllin.METHODS Human breast cancer cells were treated with polyphyllinⅠ,after which DRP1-dependent mitochondrial fission and apoptosis,mitophagy and PINK1/PARK2 pathway were evaluated.A genetic approach was employed to determine how knockdown of PINK1 with sh RNA regulates polyphyllinⅠ-induced mitophagy and apoptosis.The inhibitory effect of polyphyllinⅠon tumor growth in a breast cancer cell xenograft mouse model was also examined.RESULTS PolyphyllinⅠenhanced the stabilization of full-length PINK1at the mitochondrial surface,leading to PARK2 recruitment to mitochondria,and culminating in mitophagy.PolyphyllinⅠalso induced dephosphorylation of DRP1 at Ser637 and mitochondrial translocation of DRP1,leading to mitochondrial fission and apoptosis.Knockdown of PINK1 evidently suppressed mitophagy stimulated by polyphyllinⅠ,and markedly enhanced DRP1-dependent mitochondrial fission and apoptosis induced by polyphyl inⅠ.Furthermore,suppression of DRP1 by mdivi-1 or sh RNA inhibits PINK1 knockdown-mediated mitochondrial fragmentation and apoptosis in response to polyphyllinⅠtreatment,suggesting that depletion of PINK1 lead to mitochondrial fragmentation due to excessive fission.Our in vivo study also showed that knockdown of PINK1potentiated polyphyllinⅠ-mediated inhibition of tumor growth in a breast cancer cell xenograft mouse model.CONCLUSION Our study provides a mechanism to support the role of PINK1 in the regulation of polyphyl inⅠ-induced mitophagy and apoptosis,and suggest polyphylinⅠas a potential drug for treatment of breast cancer.

关 键 词：polyphyllin Ⅰ PINK1 MITOPHAGY DRP1 mitochondrial fission apoptosis 

分 类 号：R96[医药卫生—药理学]