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Cancer Cell. 2015 Jul 13;28(1):129-40. doi: 10.1016/j.ccell.2015.06.001.

MYC Is a Major Determinant of Mitotic Cell Fate.

Author information

1
Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
2
Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
3
Cancer Research UK Beatson Institute, Garscube Estate, Glasgow G61BD, UK.
4
School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK.
5
Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK. Electronic address: stephen.taylor@manchester.ac.uk.

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.

PMID:
26175417
PMCID:
PMC4518499
DOI:
10.1016/j.ccell.2015.06.001
[Indexed for MEDLINE]
Free PMC Article

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