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

Hee Jun Cho, Jin Koo Kim, Kwang Dong Kim, Hyun Kyung Yoon, Mi Young Cho, Yuk Pheel Park, Jun Ho Jeon, Eun Sik Lee, Seok Soo Byun, Heon Man Lim, Eun Young Song, Jong Seok Lim, Do Young Yoon, Hee Gu Lee, Yong Kyung Choe

Research output: Contribution to journalArticlepeer-review

90 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)56-66
Number of pages11
JournalCancer Letters
Volume237
Issue number1
DOIs
StatePublished - Jun 8 2006
Externally publishedYes

Keywords

  • Apoptosis
  • Bcl-2
  • Bladder cancer
  • Cisplatin
  • Resistance

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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