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.
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