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

doi:10.1016/j.ccell.2015.06.001

MYC Is a Major Determinant of Mitotic Cell Fate

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

Authors

Affiliations

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antimitotic Agents / pharmacology
Apoptosis / drug effects
Breast Neoplasms / genetics
Breast Neoplasms / pathology
Cell Line, Tumor
Colonic Neoplasms / genetics
Colonic Neoplasms / pathology
Early Growth Response Protein 1 / genetics*
Female
Gene Expression Regulation, Neoplastic / drug effects
Humans
Lung Neoplasms / genetics
Lung Neoplasms / pathology
Mice
Mitochondrial Membrane Transport Proteins
Mitosis / drug effects
Molecular Sequence Data
Neoplasms / genetics*
Neoplasms / pathology
Ovarian Neoplasms / genetics
Ovarian Neoplasms / pathology
Paclitaxel / pharmacology
Proto-Oncogene Proteins c-bcl-2 / genetics*
Proto-Oncogene Proteins c-myc / genetics*
bcl-X Protein / genetics*

Substances

Antimitotic Agents
BCL2L1 protein, human
EGR1 protein, human
Early Growth Response Protein 1
MYC protein, human
Mitochondrial Membrane Transport Proteins
Myc protein, mouse
Proto-Oncogene Proteins c-bcl-2
Proto-Oncogene Proteins c-myc
RTL10 protein, human
bcl-X Protein
Paclitaxel

Associated data

GEO/GSE68219

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding