Topham, C, Tighe, A, Ly, P, Bennett, A, Sloss, O, Nelson, L, Ridgway, RA, Huels, D, Littler, S, Schandl, C, Sun, Y, Bechi, B, Procter, DJ, Sansom, OJ, Cleveland, DW and Taylor, SS 2015, 'MYC is a major determinant of mitotic cell fate' , Cancer Cell, 28 (1) , pp. 129-140.
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Taxol and other antimitotic agents are frontline chemotherapy agents but the mechanisms responsible for patient benefit remain unclear. Following a genome-wide siRNA screen, we identified the oncogenic transcription factor Myc as a taxol sensitizer. Using time-lapse imaging to correlate mitotic behavior with cell fate, we show that Myc sensitizes cells to mitotic blockers and agents that accelerate mitotic progression. Myc achieves this by upregulating a cluster of redundant pro-apoptotic BH3-only proteins and suppressing pro-survival Bcl-xL. Gene expression analysis of breast cancers indicates that taxane responses correlate positively with Myc and negatively with Bcl-xL. Accordingly, pharmacological inhibition of Bcl-xL restores apoptosis in Myc-deficient cells. These results open up opportunities for biomarkers and combination therapies that could enhance traditional and second-generation antimitotic agents.
|Schools:||Schools > School of Environment and Life Sciences > Biomedical Research Centre|
|Journal or Publication Title:||Cancer Cell|
|Funders:||Cancer Research UK, Medical Research Council (MRC), Wellcome Trust|
|Depositing User:||C Topham|
|Date Deposited:||22 Dec 2015 15:19|
|Last Modified:||22 Dec 2015 15:19|
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