Upregulation of Bcl-2 is associated with cisplatin-resistance via inhibition of Bax translocation in human bladder cancer cells

• Published in: Cancer letters 2006-06, Vol.237 (1), p.56-66
• Main Authors: Cho, Hee Jun, Kim, Jin Koo, Kim, Kwang Dong, Yoon, Hyun Kyung, Cho, Mi-Young, Park, Yuk Pheel, Jeon, Jun Ho, Lee, Eun Sik, Byun, Seok-Soo, Lim, Heon Man, Song, Eun Young, Lim, Jong-Seok, Yoon, Do-Young, Lee, Hee Gu, Choe, Yong-Kyung
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis; Bcl-2; bcl-2-Associated X Protein - metabolism; Bladder cancer; Caspase 3; Caspase 8; Caspase 9; Caspases - metabolism; Cell Line, Tumor; Chemotherapy; Cisplatin; Cisplatin - pharmacology; Cytochromes c - metabolism; Deoxyribonucleic acid; DNA; DNA repair; Drug Resistance, Neoplasm; Enzyme Activation - drug effects; Humans; Mitochondria; Mitochondria - drug effects; Mitochondria - enzymology; Protein Transport - drug effects; Proteins; Proto-Oncogene Proteins c-bcl-2 - biosynthesis; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Resistance; RNA Interference; Studies; Tumors; Up-Regulation; Urinary Bladder Neoplasms
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2005.05.039

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.