Abstract 5579: Paclitaxel-induced apoptosis is BAK-dependent, but BAX and BIM-independent in breast tumor.

Abstract

Abstract 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. Paclitaxel stabilizes microtubules, resulting in G2/M cell cycle arrest, and continuous treatment with paclitaxel ultimately leads to cell death. However, the precise mechanisms of how this mitotic arrest triggers cell death are still unclear. When cells undergo paclitaxel-induced cell death, the BCL-2 family-dependent mitochondrial apoptotic pathway is activated. 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. 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 MCL-1 phosphorylation and subsequent 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. Citation Format: Anna V. Miller, Mark A. Hicks, Amanda C. Richardson, Jolene J. Windle, Hisashi Harada. Paclitaxel-induced apoptosis is BAK-dependent, but BAX and BIM-independent in breast tumor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5579. doi:10.1158/1538-7445.AM2013-5579