Department of Biochemistry, College of Natural Sciences, Chungnam National University, Daejeon 305-764, Republic of Korea.
Biochem Biophys Res Commun. 2010 Jan 22;391(4):1592-7. doi: 10.1016/j.bbrc.2009.12.077. Epub 2009 Dec 30.
Statins are cholesterol-lowing drugs with pleiotropic effects including cytotoxicity to cancer cells. In this study, we investigated the signaling pathways leading to apoptosis by simvastatin. Simvastatin induced cardinal features of apoptosis including increased DNA fragmentation, disruption of mitochondrial membrane potential (MMP), and increased caspase-3 activity by depleting isoprenoids in MethA fibrosarcoma cells. Interestingly, the simvastatin-induced apoptosis was accompanied by p53 stabilization involving Mdm2 degradation. The apoptosis was ameliorated in p53 knockdown clones of MethA cells as well as p53(-/-) HCT116 cells. The stabilized p53 protein translocated to mitochondria with Bax, and cytochrome c was released into cytosol. Moreover, knockdown or deficiency of p53 expression reduced both Bax translocation to mitochondria and MMP disruption in simvastatin-induced apoptosis. Taken together, these all indicate that stabilization and translocation of p53 to mitochondria is involved in Bax translocation to mitochondria in simvastatin-induced apoptosis.
他汀类药物是具有多种作用的降胆固醇药物，包括对癌细胞的细胞毒性。在这项研究中，我们通过模拟辛伐他汀研究了导致细胞凋亡的信号通路。辛伐他汀通过耗尽 MethA 纤维肉瘤细胞中的异戊二烯，诱导包括增加 DNA 片段化、破坏线粒体膜电位 (MMP) 和增加 caspase-3 活性在内的细胞凋亡的主要特征。有趣的是，辛伐他汀诱导的细胞凋亡伴随着 p53 稳定，涉及 Mdm2 降解。MethA 细胞的 p53 敲低克隆以及 p53(-/-) HCT116 细胞中的细胞凋亡得到改善。稳定的 p53 蛋白与 Bax 一起转移到线粒体，细胞色素 c 释放到细胞质中。此外，p53 表达的敲低或缺失减少了 Bax 向线粒体的易位和 MMP 在辛伐他汀诱导的细胞凋亡中的破坏。综上所述，所有这些都表明 p53 向线粒体的稳定和易位参与了 Bax 向辛伐他汀诱导的细胞凋亡中线粒体的易位。
