Abstract
Paclitaxel (Taxol)-induced cell death requires the intrinsic cell death pathway, but the specific participants and the precise mechanisms are poorly understood. Previous studies indicate that a BH3-only protein BIM (BCL-2 Interacting Mediator of cell death) plays a role in paclitaxel-induced apoptosis. We show here that BIM is dispensable in apoptosis with paclitaxel treatment using bim−/− MEFs (mouse embryonic fibroblasts), the bim−/− mouse breast tumor model, and shRNA-mediated down-regulation of BIM in human breast cancer cells. In contrast, both bak −/− MEFs and human breast cancer cells in which BAK was down-regulated by shRNA were more resistant to paclitaxel. However, paclitaxel sensitivity was not affected in bax−/− MEFs or in human breast cancer cells in which BAX was down-regulated, suggesting that paclitaxel-induced apoptosis is BAK-dependent, but BAX-independent. In human breast cancer cells, paclitaxel treatment resulted in MCL-1 degradation which was prevented by a proteasome inhibitor, MG132. A Cdk inhibitor, roscovitine, blocked paclitaxel-induced MCL-1 degradation and apoptosis, suggesting that Cdk activation at mitotic arrest could induce subsequent MCL-1 degradation in a proteasome-dependent manner. BAK was associated with MCL-1 in untreated cells and became activated in concert with loss of MCL-1 expression and its release from the complex. Our data suggest that BAK is the mediator of paclitaxel-induced apoptosis and could be an alternative target for overcoming paclitaxel resistance.
Highlights
Breast cancer is a leading cause of death among women
In order to examine the role of BIM in paclitaxel-induced cell death, we prepared mouse embryonic fibroblasts (MEFs) from wild-type and bim2/2 mice and treated with 20 nM of paclitaxel for 48 hrs
Paclitaxel-induced Apoptosis is BAK-dependent Since bax2/2bak2/2 MEFs were resistant to paclitaxel-induced cell death (Figure 1), we examined whether BAX and/or BAK were required for the cell death
Summary
Breast cancer is a leading cause of death among women. Understanding breast cancer at the molecular level is imperative for finding more effective approaches to successfully treat these patients. Microtubule inhibitors are among the most frequently used agents for breast cancer treatment, with proven efficacy in both localized and metastatic disease. Paclitaxel (Taxol) is a member of the taxane class of anti-neoplastic microtubule damaging agents and exhibits activity against a wide range of human malignancies including breast cancer [1,2]. Paclitaxel stabilizes microtubules, resulting in G2/M cell cycle arrest, and continuous treatment with paclitaxel leads to cell death. The precise mechanisms of how this mitotic arrest triggers cell death are still unclear
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