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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 over expressed, 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 over expression.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.