Dihydroartemisinin induces apoptosis preferentially via a Bim-mediated intrinsic pathway in hepatocarcinoma cells
Dihydroartemisinin induces apoptosis preferentially via a Bim-mediated intrinsic pathway in hepatocarcinoma cells
复制标题
双氢青蒿素优先通过 Bim 介导的内在途径诱导肝癌细胞凋亡
DOI：
10.1007/s10495-015-1132-2
复制
发表时间：
2015-08-01
期刊：
影响因子：
7.2
通讯作者：
Chen, Tongsheng
中科院分区：
文献类型：
--
作者：
Qin, Guiqi;Zhao, ChuBiao;Chen, Tongsheng
本研究旨在探讨青蒿素衍生物双氢青蒿素（DHA）诱导人肝癌细胞凋亡的分子机制。DHA诱导线粒体跨膜电位（Delta Im）的丧失、细胞色素c的释放、半胱天冬酶的激活和指示凋亡诱导的磷脂酰丝氨酸的外化。与沉默Bax的适度抑制作用相比，沉默巴克在很大程度上防止DHA诱导的Delta Im崩溃和凋亡，尽管DHA诱导Bax和巴克的可抑制的激活，证明了Bak介导的内在凋亡途径的关键作用。DHA不能诱导Bid裂解和从细胞质向线粒体移位，对Puma和Noxa的表达影响不大，但能增加Bim和巴克的表达，降低Mcl-1的表达。此外，DHA的细胞毒性通过沉默Bim显著降低，并且通过沉默Puma或Noxa适度但显著地降低。沉默Bim或Noxa优先减少DHA诱导的巴克活化，而沉默Puma优先减少DHA诱导的Bax活化，表明Bim和Noxa在较小程度上作为上游介质触发巴克介导的内在凋亡途径。此外，沉默Mcl-1增强DHA诱导的巴克活化和凋亡。综上所述，我们的数据表明Bim在优先调节巴克/Mcl-1变阻器介导DHA诱导的肝癌细胞凋亡中的关键作用。
This report is designed to dissect the detail molecular mechanism by which dihydroartemisinin (DHA), a derivative of artemisinin, induces apoptosis in human hepatocellular carcinoma (HCC) cells. DHA induced a loss of the mitochondrial transmemberane potential (Delta Im), release of cytochrome c, activation of caspases, and externalization of phosphatidylserine indicative of apoptosis induction. Compared with the modest inhibitory effects of silencing Bax, silencing Bak largely prevented DHA-induced Delta Im collapse and apoptosis though DHA induced a commensurable activation of Bax and Bak, demonstrating a key role of the Bak-mediated intrinsic apoptosis pathway. DHA did not induce Bid cleavage and translocation from cytoplasm to mitochondria and had little effects on the expressions of Puma and Noxa, but did increase Bim and Bak expressions and decrease Mcl-1 expression. Furthermore, the cytotoxicity of DHA was remarkably reduced by silencing Bim, and modestly but significantly reduced by silencing Puma or Noxa. Silencing Bim or Noxa preferentially reduced DHA-induced Bak activation, while silencing Puma preferentially reduced DHA-induced Bax activation, demonstrating that Bim and to a lesser extent Noxa act as upstream mediators to trigger the Bak-mediated intrinsic apoptosis pathway. In addition, silencing Mcl-1 enhanced DHA-induced Bak activation and apoptosis. Taken together, our data demonstrate a crucial role of Bim in preferentially regulating the Bak/Mcl-1 rheostat to mediate DHA-induced apoptosis in HCC cells.