辛伐他汀抑制肿瘤细胞增殖及其可能的机制  

Effects of simvastatin on the proliferation of tumor cells in vitro

作　　者：沈桂芬[1] 蒋建刚[1] 胡绍先[1] 汪道文[1] 

机构地区：[1]华中科技大学同济医学院附属同济医院内科,武汉430030

出　　处：《中华肿瘤杂志》2008年第1期21-25,共5页Chinese Journal of Oncology

基　　金：科技部国际合作资助项目（2005DFA30880）

摘　　要：目的研究辛伐他汀对肿瘤细胞增殖的抑制作用及其可能的机制。方法将U87、Hela、HCT-116（p53＋／＋）和HCT-116（p53-／-）4种肿瘤细胞在不同浓度的辛伐他汀溶液中培养48h，二苯基溴化四氮唑蓝（MTT）法检测肿瘤细胞的增殖情况；将4种肿瘤细胞在100μmol／L的辛伐他汀溶液中培养24、48、72和96h，观察肿瘤细胞的增殖情况；流式细胞仪检测辛伐他汀对4种肿瘤细胞细胞周期的影响；Westernblot法检测p21、ERK1／2、p38、JNK和Akt蛋白的表达以及ERK1／2、p38、JNK和Akt的磷酸化水平。结果与对照组和溶媒组比较，辛伐他汀可明显抑制4种肿瘤细胞的生长，并呈明显的剂量和时间依赖性（P〈0．05）；辛伐他汀使肿瘤细胞停滞于细胞周期的G1期，并且通过p53非依赖性途径上调p21的表达。Westernblot结果显示，辛伐他汀显著上调了p38和JNK的磷酸化水平，但是对信号转导通路中的蛋白激酶ERK1／2和Akt的表达和磷酸化水平并没有明显影响。结论辛伐他汀有显著的抗肿瘤作用，其作用机制可能与促进p21蛋白的表达有关，而p38和JNK也可能在辛伐他汀抑制肿瘤细胞的增殖过程中起着重要作用。Objective To investigate the antiproliferative effect of simvastatin on tumor cells and its mechanism. Methods Tumor cells U87, Hela, HCT-116 （p53 ＋/＋ ）, HCT-116 （p53-/- ） were incubated with simvastatin at different concentrations and 96 h. Cell proliferation was determined by MTT and with 100 μmol/L simvastatin for 24 h,48 h,72 h U87, HCT-116（p53 ＋/＋ ）, HCT-116（p53 -/- ） cells were incubated with simvastatin for 48 hours, and the cell cycle distributions were analyzed by flow cytometry. The levels of total p21 protein synthesis and phosphorylation of ERK1/2, p38, JNK and Akt were determined by Western blot. Results The cell growth of all the four types of tumor cells U87, Hela, HCT- 116（p53 ＋/＋ ） and HCT-116（p53 -/- ） was suppressed in a dose- and time-dependent manner （P 〈 0.05）. In addition, incubation with simvastatin arrested cells at G1 phase of the cell cycle accompanied by up-regulation of cell cycle inhibitor p21. Western blot analysis showed that simvastatin markedly increased the phosphorylation of p38 and JNK in the cells, but activities of protein kinases ERKl/2 and Akt in the intracellular signal transduction pathway remained unchanged. Conclusion Those observations suggest that statins can inhibit the proliferation of tumor cells beyond their cholesterol-lowing effect and p21, p38 and JNK may play an important role in simvastatin-induced proliferation inhibition.

关 键 词：辛伐他汀 信号转导通路 肿瘤细胞增殖 

分 类 号：R73-3[医药卫生—肿瘤]