THESIS
2015
xxiv, 209 pages : illustrations ; 30 cm
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 d...[
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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.
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