Zeng Tao, Peng Lifen, Chao Haichao, Xi Haibo, Fu Bin, Wang Yibing, Zhu Zunwei, Wang Gongxian
School of Medicine, Nanchang University, Nanchang, Jiangxi, PR China.
E.N.T. Department, The People's Hospital of Jiangxi Province, Nanchang, PR China.
Biochem Biophys Res Commun. 2015 May 8;460(3):530-6. doi: 10.1016/j.bbrc.2015.03.064. Epub 2015 Mar 19.
Bladder urothelial carcinoma (UC) accounts for approximately 5% of all cancer deaths in humans. Current treatments extend the recurrence interval but do not significantly alter patient survival. The objective of the present study was to investigate the anti-cancer effect and the underlying mechanisms of CXC195 against human UC cell line T24 cells. CXC195 inhibited the cells growth and induced caspase- and mitochondrial-dependent apoptosis in T24 cells. In addition, CXC195 triggered activation of proteins involved in ER stress signaling including GRP78, CHOP, IRE1α, TRAF2, p-ASK1 and p-JNK in T24 cells. Co-immunoprecipitation experiments showed that activation of JNK was induced by the activation of IRE1α through formation of an IRE1α-TRAF2-ASK1 complex. Knockdown of IRE1α by siRNA dramatically abrogated CXC195-induced activation of TRAF2, ASK and JNK, formation of an IRE1α-TRAF2-ASK1 complex and caspase- and mitochondrial-dependent apoptosis in T24 cells. These findings provided new insights to understand the mode of action of CXC195 in treatment of human UC.
膀胱尿路上皮癌（UC）约占人类所有癌症死亡人数的5%。目前的治疗方法延长了复发间隔，但并未显著改变患者的生存率。本研究的目的是探讨CXC195对人UC细胞系T24细胞的抗癌作用及其潜在机制。CXC195抑制T24细胞的生长，并诱导其发生半胱天冬酶和线粒体依赖性凋亡。此外，CXC195在T24细胞中触发了内质网应激信号通路相关蛋白的激活，包括GRP78、CHOP、IRE1α、TRAF2、p-ASK1和p-JNK。免疫共沉淀实验表明，IRE1α通过形成IRE1α-TRAF2-ASK1复合物激活JNK。用小干扰RNA敲低IRE1α可显著消除CXC195诱导的TRAF2、ASK和JNK的激活、IRE1α-TRAF2-ASK1复合物的形成以及T24细胞中半胱天冬酶和线粒体依赖性凋亡。这些发现为理解CXC195治疗人UC的作用模式提供了新的见解。
