title: MYC Is a Major Determinant of Mitotic Cell Fate.
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.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Topham
authors.affiliation: Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Tighe
authors.affiliation: Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Ly
authors.affiliation: Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Ailsa
authors.initials: A
authors.lastname: Bennett
authors.affiliation: Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Olivia
authors.initials: O
authors.lastname: Sloss
authors.affiliation: Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Louisa
authors.initials: L
authors.lastname: Nelson
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Glasgow G61BD, UK.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Ridgway
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Glasgow G61BD, UK.
authors.forename: David
authors.initials: D
authors.lastname: Huels
authors.affiliation: Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Samantha
authors.initials: S
authors.lastname: Littler
authors.affiliation: Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Claudia
authors.initials: C
authors.lastname: Schandl
authors.affiliation: Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.affiliation: School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Bechi
authors.affiliation: School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Procter
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Glasgow G61BD, UK.
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.affiliation: Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
authors.affiliation: Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK. Electronic address: stephen.taylor@manchester.ac.uk.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Taylor
mesh_terms: D000818:Animals; D050256:Antimitotic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology; D051766:Early Growth Response Protein 1 / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D051379:Mice; D033681:Mitochondrial Membrane Transport Proteins; D008938:Mitosis / Q000187:drug effects; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D051020:bcl-X Protein / Q000235:genetics*
chemical_list: D050256:Antimitotic Agents; C494811:BCL2L1 protein, human; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C489427:MYC protein, human; D033681:Mitochondrial Membrane Transport Proteins; C489428:Myc protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; C581062:RTL10 protein, human; D051020:bcl-X Protein; D017239:Paclitaxel