| Abstract |
Sustained activation of the spindle assembly checkpoint (SAC) arrests cells in mitosis, resulting in mitotic cell death; therefore, SAC-activating drugs have been developed and clinically used as anti-cancer agents. However, some mitotic cells exhibit mitotic slippage, an event of mitotic exit without SAC satisfaction, and less sensitivity to these drugs. For developing efficient anti-cancer therapy, it is required to reveal the mechanism underlying the cell fate determination between cell death and mitotic slippage. In this study, we found that oxysterol-binding protein-like 11 (OSBPL11) is important for cell fate determination during mitotic arrest. OSBPL11 knockdown accelerates mitotic slippage and instead represses cell death during mitotic arrest by treatment with the Eg5 inhibitor S-trityl-l-cysteine (STLC), although the duration from mitotic entry to slippage or death is not altered. OSBPL11 knockdown exhibits a similar phenotype in paclitaxel-treated cells. Cyclin B1 levels are decreased in OSBPL11-knockdown mitotic cells. Treatment with the APC/C inhibitor proTAME mitigates both the decrease in the cyclin B1 levels and the acceleration of mitotic slippage caused by OSBPL11 knockdown. Although the OSBPL11 wild type could mitigate the acceleration of mitotic slippage and the repression of cell death induced by OSBPL11 knockdown, mutants lacking the lipid transport and lipid binding activities could not. Furthermore, OSBPL11 knockdown promotes survival upon STLC and paclitaxel treatments. These results suggest that OSBPL11 represses mitotic slippage and accelerates cell death during mitotic arrest in a manner dependent on both lipid transport and lipid binding activities, promoting the cytotoxic effect of SAC-activating drugs.
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