Resistance to anti-microtubule drug-induced cell death is determined by regulation of BimEL expression

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Abstract

Anti-microtubule agents are frequently used as anticancer therapeutics. Cell death induced by these agents is considered to be due to sustained mitotic arrest caused by the activation of spindle assembly checkpoint (SAC). However, some cell types are resistant to mitotic cell death. Cells’ ability to escape mitotic arrest (mitotic slippage) is thought to be a major mechanism contributing to this resistance. Here, we show that resistance to cell death induced by anti-mitotic agents is not linked to cells’ capacity to undergo mitotic slippage as generally believed but is dependent on the state of BimEL regulation during mitosis. While transcriptional repression of BimEL in the mitotic death-resistant cells involves polycomb repressive complex 2 (PRC2)-mediated histone trimethylation, the BimEL protein is destabilized by cullin 1/4A-βTrCP-dependent degradation involving activation of cullin 1/4A by neddylation. These results imply that pharmacological augmentation of BimEL activity in anti-microtubule drug-resistant tumors may have important therapeutic implications.

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Acknowledgements

We thank the members of the US laboratory for helpful discussions and the mouse model unit (IMCB, Singapore) for kindly providing the PLKO.1 vector and lentiviral packaging vectors. The U.S. lab is supported by the Biomedical Research Council of A*STAR (Agency for Science, Technology and Research), Singapore.

Author contributions

WR, GV and US conceived and designed the experiments. WR and GV performed the experiments. RMS, LC, LCW, AJ and KP assisted in some of the experiments. WR, GV and US analyzed the data. WR, GV and US wrote the paper.

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Correspondence to Uttam Surana.

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