MYC Is a Major Determinant of Mitotic Cell Fate

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2015 Jul 16

PMID 26175417

Citations 82

Authors

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

Affiliations

Soon will be listed here.

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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References

Gascoigne K, Taylor S . Cancer cells display profound intra- and interline variation following prolonged exposure to antimitotic drugs. Cancer Cell. 2008; 14(2):111-22. DOI: 10.1016/j.ccr.2008.07.002. View

Eilers M, Eisenman R . Myc's broad reach. Genes Dev. 2008; 22(20):2755-66. PMC: 2751281. DOI: 10.1101/gad.1712408. View

Upreti M, Galitovskaya E, Chu R, Tackett A, Terrano D, Granell S . Identification of the major phosphorylation site in Bcl-xL induced by microtubule inhibitors and analysis of its functional significance. J Biol Chem. 2008; 283(51):35517-25. PMC: 2602892. DOI: 10.1074/jbc.M805019200. View

Keen N, Taylor S . Mitotic drivers--inhibitors of the Aurora B Kinase. Cancer Metastasis Rev. 2009; 28(1-2):185-95. DOI: 10.1007/s10555-009-9184-9. View

Den Hollander J, Rimpi S, Doherty J, Rudelius M, Buck A, Hoellein A . Aurora kinases A and B are up-regulated by Myc and are essential for maintenance of the malignant state. Blood. 2010; 116(9):1498-505. PMC: 2938839. DOI: 10.1182/blood-2009-11-251074. View

Dumontet C, Jordan M . Microtubule-binding agents: a dynamic field of cancer therapeutics. Nat Rev Drug Discov. 2010; 9(10):790-803. PMC: 3194401. DOI: 10.1038/nrd3253. View

Radulescu S, Ridgway R, Appleton P, Kroboth K, Patel S, Woodgett J . Defining the role of APC in the mitotic spindle checkpoint in vivo: APC-deficient cells are resistant to Taxol. Oncogene. 2010; 29(49):6418-27. PMC: 3016607. DOI: 10.1038/onc.2010.373. View

Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith W, Fedorov O . Selective inhibition of BET bromodomains. Nature. 2010; 468(7327):1067-73. PMC: 3010259. DOI: 10.1038/nature09504. View

Huang H, Mitchison T, Shi J . Stochastic competition between mechanistically independent slippage and death pathways determines cell fate during mitotic arrest. PLoS One. 2011; 5(12):e15724. PMC: 3006339. DOI: 10.1371/journal.pone.0015724. View

10.

Boone D, Qi Y, Li Z, Hann S . Egr1 mediates p53-independent c-Myc-induced apoptosis via a noncanonical ARF-dependent transcriptional mechanism. Proc Natl Acad Sci U S A. 2010; 108(2):632-7. PMC: 3021028. DOI: 10.1073/pnas.1008848108. View

11.

Shi J, Zhou Y, Huang H, Mitchison T . Navitoclax (ABT-263) accelerates apoptosis during drug-induced mitotic arrest by antagonizing Bcl-xL. Cancer Res. 2011; 71(13):4518-26. PMC: 3129452. DOI: 10.1158/0008-5472.CAN-10-4336. View

12.

Campone M, Noel B, Couriaud C, Grau M, Guillemin Y, Gautier F . c-Myc dependent expression of pro-apoptotic Bim renders HER2-overexpressing breast cancer cells dependent on anti-apoptotic Mcl-1. Mol Cancer. 2011; 10:110. PMC: 3175201. DOI: 10.1186/1476-4598-10-110. View

13.

Janssen A, van der Burg M, Szuhai K, Kops G, Medema R . Chromosome segregation errors as a cause of DNA damage and structural chromosome aberrations. Science. 2011; 333(6051):1895-8. DOI: 10.1126/science.1210214. View

14.

Mitchison T . The proliferation rate paradox in antimitotic chemotherapy. Mol Biol Cell. 2012; 23(1):1-6. PMC: 3248889. DOI: 10.1091/mbc.E10-04-0335. View

15.

Komlodi-Pasztor E, Sackett D, Tito Fojo A . Inhibitors targeting mitosis: tales of how great drugs against a promising target were brought down by a flawed rationale. Clin Cancer Res. 2012; 18(1):51-63. DOI: 10.1158/1078-0432.CCR-11-0999. View

16.

Kessler J, Kahle K, Sun T, Meerbrey K, Schlabach M, Schmitt E . A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis. Science. 2011; 335(6066):348-53. PMC: 4059214. DOI: 10.1126/science.1212728. View

17.

Sodir N, Evan G . Finding cancer's weakest link. Oncotarget. 2011; 2(12):1307-13. PMC: 3282087. DOI: 10.18632/oncotarget.396. View

18.

Orth J, Loewer A, Lahav G, Mitchison T . Prolonged mitotic arrest triggers partial activation of apoptosis, resulting in DNA damage and p53 induction. Mol Biol Cell. 2011; 23(4):567-76. PMC: 3279386. DOI: 10.1091/mbc.E11-09-0781. View

19.

Garnett M, Edelman E, Heidorn S, Greenman C, Dastur A, Lau K . Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature. 2012; 483(7391):570-5. PMC: 3349233. DOI: 10.1038/nature11005. View

20.

Hayashi M, Cesare A, Fitzpatrick J, Lazzerini-Denchi E, Karlseder J . A telomere-dependent DNA damage checkpoint induced by prolonged mitotic arrest. Nat Struct Mol Biol. 2012; 19(4):387-94. PMC: 3319806. DOI: 10.1038/nsmb.2245. View