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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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