Functions of the BCL-2 family in mitotic cell death

Abstract

Antimitotic drugs are among the most important chemotherapeutic agents available. However, abnormal mitotic exit mechanisms including mitotic slippage occur in antimitotic drug-treated cells and may lead to drug resistance or tumor relapse. Therefore, it is important to understand how mitotic cell death is regulated at the molecular level. The BCL-2 protein family regulates apoptosis by controlling mitochondria outer membrane integrity. This study systematically investigated the contribution of anti-apoptotic BCL-2-like proteins in mitotic cell death. The effects of depletion of individual BCL-2 family members on mitotic cell fates were evaluated using live-cell imaging. These studies indicated that multiple BCL-2-like proteins were involved in paclitaxel-induced mitotic cell death. Overexpression of these proteins repressed mitotic catastrophe induced by spindle poisons, which did not lead to the enhancement of long-term survival. During prolonged mitotic arrest, all anti-apoptotic BCL-2-like proteins except BCL-W underwent post-transcriptional modification or degradation. Despite the high stability of BCL-W during mitotic arrest, the level of BCL-W determined mitotic cell fates in the cells exposed to several antimitotic drugs. Importantly, the level of endogenous BCL-W varied significantly in different cell lines, suggesting that it may be an important variable in determining the susceptibility of cells to antimitotic drugs. In conclusion, this study reveals that multiple anti-apoptotic BCL-2-like proteins determine mitotic cell fates following treatment with anti-mitotic drugs. Since BCL-2 inhibitors are being evaluated as potential anticancer agents, this study also highlighted the molecular basis of synergism between BCL-2 inhibitors and antimitotic drugs.

Date of Award	2015
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology