Abstract
Microtubule inhibitors including taxanes and vinca alkaloids are among the most widely used anticancer agents. Disrupting the microtubules activates the spindle-assembly checkpoint and traps cells in mitosis. Whether cells subsequently undergo mitotic cell death is an important factor for the effectiveness of the anticancer agents. Given that apoptosis accounts for the majority of mitotic cell death induced by microtubule inhibitors, we performed a systematic study to determine which members of the anti-apoptotic BCL-2 family are involved in determining the duration of mitotic block before cell death or slippage. Depletion of several anti-apoptotic BCL-2-like proteins significantly shortened the time before apoptosis. Among these proteins, BCL-W has not been previously characterized to play a role in mitotic cell death. Although the expression of BCL-W remained constant during mitotic block, it varied significantly between different cell lines. Knockdown of BCL-W with siRNA or disruption of the BCL-W gene with CRISPR-Cas9 speeded up mitotic cell death. Conversely, overexpression of BCL-W delayed mitotic cell death, extending the mitotic block to allow mitotic slippage. Taken together, these results showed that BCL-W contributes to the threshold of anti-apoptotic activity during mitosis.
Highlights
Mitotic entry is driven by CDK1 and its activator cyclin B1
After ensuring the siRNAs could reduce the expression of anti-apoptotic BCL-2-like proteins and did not affect unperturbed mitosis, we examined their effects on mitotic cell death
Given the importance of BCL-W in mitotic cell death, we examined the expression of BCL-W during microtubule inhibitor-mediated mitotic blocks
Summary
Mitotic entry is driven by CDK1 and its activator cyclin B1. Destruction of cyclin B1 by APC/C-dependent ubiquitination provides a cue for mitotic exit. As APC/C activation occurs only after the spindle-assembly checkpoint is satisfied, agents that attenuate microtubules depolymerization (e.g. taxanes) or polymerization (e.g. vinca alkaloid) promote cell cycle arrest in mitosis [1]. The fate of cells after protracted mitotic block varies greatly between different cell lines as well as between individual cells from the same cell line [3]. The current model of how the cell fate is determined is based on two stochastically competing networks, one controlling mitotic slippage and the other mitotic cell death. Whether a cell dies or undergoes slippage during a prolonged mitotic block is the consequence of whether the cell first breaches the threshold of cell death or mitotic slippage, respectively
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