Polyphyllin I induces mitophagic and apoptotic cell death in human breast cancer cells by increasing mitochondrial PINK1 levels.
Polyphyllin I induces mitophagic and apoptotic cell death in human breast cancer cells by increasing mitochondrial PINK1 levels.
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Polyphyllin I 通过增加线粒体 PINK1 水平诱导人乳腺癌细胞线粒体自噬和凋亡细胞死亡
DOI：
10.18632/oncotarget.14413
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发表时间：
2017-02-07
期刊：
影响因子：
--
通讯作者：
Gao N
中科院分区：
文献类型：
--
作者：
Li GB;Fu RQ;Shen HM;Zhou J;Hu XY;Liu YX;Li YN;Zhang HW;Liu X;Zhang YH;Huang C;Zhang R;Gao N
从巴黎根茎中提取的天然化合物polyphyllin I的抗乳腺癌作用的分子机制尚未完全了解。在本研究中，我们发现，polyphyllin I诱导DRP 1的线粒体易位的DRP 1在Ser 637去磷酸化，导致线粒体分裂，细胞色素c从线粒体释放到胞质溶胶，并最终凋亡。Polyphyllin I还增加了全长PINK 1在线粒体表面的稳定性，导致PARK 2、P62、泛素和LC 3B-II向线粒体的募集，并在线粒体自噬中达到高潮。PINK 1基因敲低显著抑制了polyphyllin I诱导的线粒体自噬，并增强了polyphyllin I诱导的、依赖于DRP 1的线粒体分裂和凋亡。此外，通过mdivi-1或shRNA抑制MRP 1可以抑制PINK 1敲除/多叶林I诱导的线粒体断裂和细胞凋亡，这表明PINK 1缺失导致过度分裂，随后导致线粒体断裂。体内研究证实，polyphyllin I极大地抑制了MDA-MB-231异种移植物中的肿瘤生长并诱导了细胞凋亡，并且这些作用通过PINK 1敲低而增强。这些数据描述了PINK 1促进polyphyllin I诱导的线粒体自噬和细胞凋亡的机制，并表明polyphyllin I可能是治疗乳腺癌的有效药物。
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.