title: IRE1α-TRAF2-ASK1 complex-mediated endoplasmic reticulum stress and mitochondrial dysfunction contribute to CXC195-induced apoptosis in human bladder carcinoma T24 cells.
abstract: 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.
authors: School of Medicine, Nanchang University, Nanchang, Jiangxi, PR China. Electronic address: zengtaonanchang@163.com.
authors: Tao
authors: T
authors: Zeng
authors: E.N.T. Department, The People's Hospital of Jiangxi Province, Nanchang, PR China.
authors: Lifen
authors: L
authors: Peng
authors: School of Medicine, Nanchang University, Nanchang, Jiangxi, PR China.
authors: Haichao
authors: H
authors: Chao
authors: Institute of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, PR China.
authors: Haibo
authors: H
authors: Xi
authors: Institute of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, PR China.
authors: Bin
authors: B
authors: Fu
authors: Institute of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, PR China.
authors: Yibing
authors: Y
authors: Wang
authors: Department of Urology, The People's Hospital of Jiangxi Province, Nanchang, PR China.
authors: Zunwei
authors: Z
authors: Zhu
authors: Institute of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, PR China.
authors: Gongxian
authors: G
authors: Wang
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D008928:Mitochondria / Q000502:physiology*; D018384:Oxidative Stress; D010879:Piperazines / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011719:Pyrazines / Q000378:metabolism*; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000473:pathology*
chemical_list: C552200:CXC 195; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D010879:Piperazines; D011719:Pyrazines; D047992:TNF Receptor-Associated Factor 2; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D004722:Endoribonucleases
keywords: Apoptosis; Bladder urothelial carcinoma; CXC195; ER stress; IRE1a-TRAF2-ASK1 complex; JNK