Regulation of Bax by c-Jun NH2-terminal kinase and Bcl-xL in vinblastine-induced apoptosis

Rong Chu, Meenakshi Upreti, Wen Xing Ding, Xiao Ming Yin, Timothy C. Chambers

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Microtubule inhibitors, such as vinblastine, are widely used in cancer chemotherapy. Vinblastine exerts its antitumor effect by inducing apoptosis. In KB-3 cells, we have shown previously that vinblastine activates c-Jun NH2-terminal protein kinase (JNK) and causes Bax mitochondrial translocation and activation. In this study, we sought to test the hypothesis that JNK and Bcl-xL act as positive and negative regulators, respectively, of Bax translocation. The JNK inhibitor SP600125 inhibited vinblastine-induced JNK activation and in concert inhibited Bax mitochondrial translocation, Bax oligomerization, and Bax activation. Furthermore, the JNK inhibitor blocked vinblastine-induced apoptosis. The ability of vinblastine to induce Bax translocation and the inhibitory effect of SP600125 were confirmed in cells stably expressing GFP-Bax. However, if transiently overexpressed, Bax localized to the mitochondria, and this was associated with loss of viability and subsequent cell death. If Bcl-xL was co-expressed with Bax, the cells readily tolerated Bax overexpression. Indeed, physical interaction between Bcl-xL and Bax but not Bak was demonstrated by co-immunoprecipitation. These findings provide novel insight into the role of Bax and its regulation in vinblastine-induced apoptosis.

Original languageEnglish (US)
Pages (from-to)241-248
Number of pages8
JournalBiochemical Pharmacology
Volume78
Issue number3
DOIs
StatePublished - Aug 1 2009

Keywords

  • Apoptosis
  • Bax
  • Bcl-xL
  • JNK
  • Vinblastine

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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