Chang Hang-Lung, Chen Chih-Yu, Hsu Ya-Fen, Kuo Wen-Shin, Ou George, Chiu Pei-Ting, Huang Yu-Han, Hsu Ming-Jen
Department of Surgery, Landseed Hospital, Taoyuan, Taiwan.
Biochim Biophys Acta. 2013 Aug;1830(8):4053-64. doi: 10.1016/j.bbagen.2013.04.011. Epub 2013 Apr 12.
Statins, the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors with cholesterol-lowering properties, were recently shown to exhibit anti-cancer effects. However, the molecular mechanism underlying statin-induced cancer cell death remains to be elucidated. Elevated level of survivin is often found over-expressed in human cancers and has been implicated in the progression of tumorigenesis. Given its central role in cell division and action as an apoptosis suppressor, survivin represents a potential molecular target in cancer management.
In this study, we explored the underlying mechanisms in simvastatin-induced HCT116 colorectal cancer cell apoptosis.
Simvastatin decreased cell viability and induced cell apoptosis in HCT116 cells. These results are associated with the modulation of p21(cip/Waf1) and survivin. Survivin knockdown using survivin siRNAs also decreased cell viability and induced cell apoptosis. Simvastatin's actions on p21(cip/Waf1), survivin and apoptosis were reduced in p53 null HCT116 cells. Simvastatin caused an increase in p53 phosphorylation and acetylation. In addition, simvastatin activated p38 mitogen-activated protein kinase (p38MAPK), whereas an inhibitor of p38MAPK signaling abrogated simvastatin's effects of increasing p53 and p21(cip/Waf1) promoter luciferase activity. Cell viability and survivin promoter luciferase activity in the presence of simvastatin were also restored by p38MAPK inhibitor. Furthermore, Sp1 binding to the survivin promoter region decreased while p53 and p63 binding to the promoter region increased after simvastatin exposure.
Simvastatin activates the p38MAPK-p53-survivin cascade to cause HCT116 colorectal cancer cell apoptosis.
This study delineates, in part, the underlying mechanisms of simvastatin in decreasing survivin and subsequent colorectal cancer cell apoptosis.
他汀类药物是具有降胆固醇特性的3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂，最近显示出具有抗癌作用。然而，他汀类药物诱导癌细胞死亡的分子机制仍有待阐明。Survivin水平升高在人类癌症中经常过度表达，并与肿瘤发生进展有关。鉴于其在细胞分裂中的核心作用以及作为凋亡抑制因子的作用，Survivin是癌症治疗中的一个潜在分子靶点。
在本研究中，我们探讨了辛伐他汀诱导HCT116结肠癌细胞凋亡的潜在机制。
辛伐他汀降低了HCT116细胞的活力并诱导细胞凋亡。这些结果与p21（cip/Waf1）和Survivin的调节有关。使用Survivin siRNA敲低Survivin也降低了细胞活力并诱导细胞凋亡。在p53缺失的HCT116细胞中，辛伐他汀对p21（cip/Waf1）、Survivin和凋亡的作用减弱。辛伐他汀导致p53磷酸化和乙酰化增加。此外，辛伐他汀激活p38丝裂原活化蛋白激酶（p38MAPK），而p38MAPK信号抑制剂消除了辛伐他汀增加p53和p21（cip/Waf1）启动子荧光素酶活性的作用。p38MAPK抑制剂也恢复了辛伐他汀存在时的细胞活力和Survivin启动子荧光素酶活性。此外，辛伐他汀处理后，Sp1与Survivin启动子区域的结合减少，而p53和p63与启动子区域的结合增加。
辛伐他汀激活p38MAPK-p53-Survivin级联反应导致HCT116结肠癌细胞凋亡。
本研究部分阐述了辛伐他汀降低Survivin及随后结肠癌细胞凋亡的潜在机制。
