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MYC Is a Major Determinant of Mitotic Cell Fate.

  • Author(s): Topham, Caroline;
  • Tighe, Anthony;
  • Ly, Peter;
  • Bennett, Ailsa;
  • Sloss, Olivia;
  • Nelson, Louisa;
  • Ridgway, Rachel A;
  • Huels, David;
  • Littler, Samantha;
  • Schandl, Claudia;
  • Sun, Ying;
  • Bechi, Beatrice;
  • Procter, David J;
  • Sansom, Owen J;
  • Cleveland, Don W;
  • Taylor, Stephen S
  • et al.
Abstract

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.

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