索拉非尼通过抑制WNT信号通路诱导白血病细胞株U937凋亡  

Sorafenib Induces Apoptosis of U937 Cells via Inhibiting WNT Signal Pathway

作　　者：肖若芝[1,2] 陈琰[1,2] 王立琳[1,2] 阮星星[1] 何程明[1,2] 熊慕珺[1,2] 林东军[1,2] 

机构地区：[1]中山大学附属第三医院血液科 [2]血液病研究所,广东广州510630

出　　处：《中国实验血液学杂志》2011年第2期353-357,共5页Journal of Experimental Hematology

基　　金：广东省科技计划项目,编号355010082006B

摘　　要：本研究观察多激酶活性抑制药物索拉非尼对急性白血病细胞株U937细胞增殖活力的影响及诱导凋亡的作用,并探讨其可能的作用机制。以不同浓度的索拉非尼作用于U937细胞48小时后,使用细胞计数试剂盒-8(CCK-8)检测细胞增殖活力变化;Annexin V/PI染色后通过流式细胞仪观察索拉非尼对U937细胞株的促凋亡作用;PI染色后利用流式细胞仪分析细胞周期中各期细胞比例变化;Western blot检测GSK-3β、β-catenin、Cyclin-D1蛋白表达变化。结果表明,同对照组相比较,索拉非尼以浓度依赖方式抑制U937细胞增殖,使细胞阻滞于G1/G0期并促进其凋亡(p<0.05)。Western blot检测结果显示,与索拉非尼处理前后相比,WNT通路中失活型GSK-3β蛋白、β-catenin及cyclinD1表达均下调,并呈现出浓度依赖性。使用GSK-3β抑制剂氯化锂上调失活型GSK-3β蛋白后仍得出同样趋势(p<0.05)。结论:索拉非尼通过减少WNT信号通路负向调节蛋白GSK-3β失活,进而下调β-catenin,cyclin-D1水平,使U937细胞阻滞于G1/G0期并促进其凋亡。This study was aimed to investigate the effect of multikinase inhibitor sorafenib on the proliferation and apoptosis of U937 cells and its possible mechanism.U937 cells were treated with different concentrations of sorafenib for 48 hours.Cell viability was determined by Cell Counting Kit-8;cell apoptosis and cell ratio in cell cycle were detected by flow cytometry with Annexin V/PI staining and PI staining respectively;expressions of GSK-3β,β-catenin and cyclin-D1 were assayed by Western blot.The results showed that the proliferation of U937 cells was inhibited by sorafenib in a dose-dependent manner（p〈0.05）.Sorafenib induced cell apoptosis and cell cycle G1/G0 arrest.Compared with results of Western blot before treatment,expression of inactivated GSK-3β,β-catenin and Cyclin-D1 down-regulated in a dose-dependent manner after treatment with sorafenib,this same changes were observed after up-regulation of inactivated GSK-3β by LiCl（p〈0.05）.It is concluded that sorafenib inhibites the proliferation of U937 cells and induces cell apoptosis through reducing negative regulation of WNT signal pathway on inactivated GSK-3β and down-regulating β-catenin and cyclin-D1 level,which result in U937 cell cycle G1/G0 arrest.

关 键 词：白血病 细胞增殖 细胞凋亡 U937细胞 索拉非尼 

分 类 号：R733.71[医药卫生—肿瘤] R979.1[医药卫生—临床医学]