Matrine induces caspase-independent program cell death in hepatocellular carcinoma through bid-mediated nuclear translocation of apoptosis inducing factor.
Matrine induces caspase-independent program cell death in hepatocellular carcinoma through bid-mediated nuclear translocation of apoptosis inducing factor.
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苦参碱通过 bid 介导的凋亡诱导因子核易位诱导肝细胞癌中不依赖 caspase 的程序性细胞死亡
DOI：
10.1186/1476-4598-13-59
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发表时间：
2014-03-16
期刊：
影响因子：
37.3
通讯作者：
Hu T
中科院分区：
文献类型：
--
作者：
Zhou H;Xu M;Gao Y;Deng Z;Cao H;Zhang W;Wang Q;Zhang B;Song G;Zhan Y;Hu T
中国的临床药物苦参碱已被用于治疗病毒性肝炎、心律失常和皮肤炎。苦参碱还通过其触发癌细胞死亡的能力显示出化疗潜力。然而，其中涉及的机制在很大程度上仍不清楚。本研究旨在探讨苦参碱诱导人肝癌细胞死亡的主要决定因素。以人肝癌细胞株HepG2和人肝癌裸鼠移植瘤为模型，研究苦参碱对肝癌的作用。我们发现，苦参碱处理的HepG2细胞发生caspase依赖性和非依赖性程序性细胞死亡(PCD)，并伴有线粒体跨膜电位降低和ROS生成增加。进一步的研究表明，AIF从线粒体释放到细胞核，沉默AIF可减少苦参碱诱导的caspase非依赖性PCD。此外，Bid抑制剂BI-6C9、Bid靶向siRNA和ROS清除剂TIron可阻止AIF核转位以及随后的细胞死亡。在体内研究中，苦参碱显著抑制裸鼠肿瘤生长，并使AIF从线粒体释放到细胞核中。这些数据表明，苦参碱通过Bid介导的AIF易位，有效地诱导了HepG2细胞中caspase非依赖的PCD。
Matrine, a clinical drug in China, has been used to treat viral hepatitis, cardiac arrhythmia and skin inflammations. Matrine also exhibits chemotherapeutic potential through its ability to trigger cancer cell death. However, the mechanisms involved are still largely unknown. The objective of this study was to investigate the major determinant for the cell death induced by matrine in human hepatocellular carcinoma. We use human hepatocellular carcinoma cell line HepG2 and human hepatocellular carcinoma xenograft in nude mice as models to study the action of matrine in hepatocellular cancers. We found that caspase-dependent and -independent Program Cell Death (PCD) occurred in matrine-treated HepG2 cells, accompanied by the decreasing of mitochondrial transmembrane potential and the increasing ROS production. Further studies showed that AIF released from the mitochondria to the nucleus, and silencing of AIF reduced the caspase-independent PCD induced by matrine. What’s more, AIF nuclear translocation, and the subsequent cell death as well, was prevented by Bid inhibitor BI-6C9, Bid-targeted siRNA and ROS scavenger Tiron. In thein vivostudy, matrine significantly attenuated tumor growth with AIF release from mitochondria into nucleus in nude mice. These data imply that matrine potently induce caspase-independent PCD in HepG2 cells through Bid-mediated AIF translocation.
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影响因子：
37.3
作者：
Tang PM;Zhang DM;Xuan NH;Tsui SK;Waye MM;Kong SK;Fong WP;Fung KP
通讯作者：
Fung KP
影响因子：
5.4
作者：
Dai, Zhi-jun;Gao, Jie;Guan, Hai-tao
通讯作者：
Guan, Hai-tao
影响因子：
8
作者：
Candé, C;Vahsen, N;Kroemer, G
通讯作者：
Kroemer, G
影响因子：
11.2
作者：
Kang, YH;Yi, MJ;Lee, SJ
通讯作者：
Lee, SJ
AIF介导的caspase非依赖性坏死作用需要ATM和DNA-PK诱导的组蛋白H2AX Ser139磷酸化。
影响因子：
9
作者：
Baritaud, M.;Cabon, L.;Delavallee, L.;Galan-Malo, P.;Gilles, M-E;Brunelle-Navas, M-N;Susin, S. A.
通讯作者：
Susin, S. A.