MYC Is a Major Determinant of Mitotic Cell Fate

Caroline Topham, Anthony Tighe, Peter Ly, Ailsa Bennett, Olivia Sloss, Louisa Nelson, Rachel A. Ridgway, David Huels, Samantha Littler, Claudia Schandl, Ying Sun, Beatrice Bechi, David J. Procter, Owen J. Sansom, Don W. Cleveland, Stephen S. Taylor

Research output: Contribution to journalArticle

57 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)129-140
Number of pages12
JournalCancer Cell
Volume28
Issue number1
DOIs
StatePublished - Jul 13 2015
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Topham, C., Tighe, A., Ly, P., Bennett, A., Sloss, O., Nelson, L., Ridgway, R. A., Huels, D., Littler, S., Schandl, C., Sun, Y., Bechi, B., Procter, D. J., Sansom, O. J., Cleveland, D. W., & Taylor, S. S. (2015). MYC Is a Major Determinant of Mitotic Cell Fate. Cancer Cell, 28(1), 129-140. https://doi.org/10.1016/j.ccell.2015.06.001