Upregulation of Bcl-2 is associated with cisplatin-resistance via inhibition of Bax translocation in human bladder cancer cells
Upregulation of Bcl-2 is associated with cisplatin-resistance via inhibition of Bax translocation in human bladder cancer cells
复制标题
DOI：
10.1016/j.canlet.2005.05.039
复制
发表时间：
2006-06-08
期刊：
影响因子：
9.7
通讯作者：
Choe, Yong-Kyung
中科院分区：
文献类型：
--
作者：
Cho, Hee Jun;Kim, Jin Koo;Choe, Yong-Kyung
顺铂在癌症化疗中的疗效受到耐药性发展的限制。为了阐明顺铂耐药的分子基础，我们比较了顺铂诱导的人膀胱癌亲本细胞株T24及其耐药亚克隆T24R2的凋亡反应。在T24细胞中，顺铂诱导细胞凋亡，激活caspase-8、-9、-3和poly（adp -核糖）聚合酶裂解。Fas、FasL、FADD的表达水平未因顺铂治疗而改变。此外，fas中和抗体和FADD显性阴性突变体均不影响顺铂诱导的细胞凋亡。亚细胞组分的Western blot分析显示，顺铂诱导Bax和细胞色素c的重新分布。因此，顺铂在T24细胞中以死亡受体独立和线粒体依赖的方式引起细胞凋亡。相反，过表达的Bcl-2蛋白抑制顺铂诱导的Bax易位及其在T24R2中的下游事件。RNAi下调Bcl-2可增强Bax和细胞色素c的再分布，逆转顺铂耐药。我们的研究结果表明Bcl-2的上调有助于顺铂耐药的发展，使用靶向Bcl-2基因的siRNA可能为逆转膀胱癌对顺铂的耐药提供潜在的工具。2005爱思唯尔爱尔兰有限公司版权所有。
The efficacy of cisplatin in cancer chemotherapy is limited by the development of resistance. To elucidate the molecular basis of resistance to cisplatin, we compared cisplatin-induced apoptotic responses of the parental human bladder cancer cell line, T24 and its resistant subclone, T24R2. In T24 cells, cisplatin induce apoptosis and the activation of caspase-8, -9 and -3 and poly(ADP-ribose) polymerase cleavage. The expression levels of Fas, FasL, and FADD were not changed by the treatment with cisplatin. Furthermore, neither Fas-neutralizing antibody nor dominant negative mutant of FADD affected cisplatin-induced apoptosis. Western blot analysis of subcellular fractions showed that cisplatin induced redistribution of Bax and cytochrome c. Thus, cisplatin causes apoptosis in a death receptor-independent and mitochondria-dependent fashion in T24 cells. In contrast, overexpressed Bcl-2 protein inhibited cisplatin-induced Bax translocation and its downstream events in T24R2. Downregulation of Bcl-2 by RNAi potentiated the redistribution of Bax and cytochrome c and reversed cisplatin-resistance. Our results indicate that upregulation of Bcl-2 contributes to the development of cisplatin-resistance and usage of siRNA which targets the Bcl-2 gene may offer a potential tool to reverse the resistance to cisplatin in bladder cancer. (c) 2005 Elsevier Ireland Ltd. All rights reserved.