Anti-microtubule agents activate the spindle-assembly checkpoint by perturbing spindle formation and trapping cells in mitosis. Whether cells undergo mitotic cell death subsequently is an important factor in determining the efficacy of these drugs. BCL-2 family members regulate apoptosis through controlling the integrity of mitochondria outer membrane. I found that although the expression of BCL-W remained constant during mitotic arrest, disruption of the BCL-W gene accelerated mitotic cell death. Furthermore, ABT-263 only acted synergistically with anti-mitotic drugs when BCL-W was present. Collectively, my results revealed that BCL-W is a regulator of mitotic cell death and a crucial target of ABT-263. MCL-1 and A1 underwent rapid proteasome-dependent degradation during mitotic arrest...[ Read more ]

Anti-microtubule agents activate the spindle-assembly checkpoint by perturbing spindle formation and trapping cells in mitosis. Whether cells undergo mitotic cell death subsequently is an important factor in determining the efficacy of these drugs. BCL-2 family members regulate apoptosis through controlling the integrity of mitochondria outer membrane. I found that although the expression of BCL-W remained constant during mitotic arrest, disruption of the BCL-W gene accelerated mitotic cell death. Furthermore, ABT-263 only acted synergistically with anti-mitotic drugs when BCL-W was present. Collectively, my results revealed that BCL-W is a regulator of mitotic cell death and a crucial target of ABT-263. MCL-1 and A1 underwent rapid proteasome-dependent degradation during mitotic arrest. Furthermore, upregulation of both MCL-1 and A1 protected cells from microtubule inhibitors-induced cell death. Taken together, these data highlight the molecular basis of interactions between BCL-2 family members and antimitotic drugs.