The Fcp1-Wee1-Cdk1 axis affects spindle assembly checkpoint robustness and sensitivity to antimicrotubule cancer drugs

Cell Death and Differentiation
R ViscontiD Grieco

Abstract

To grant faithful chromosome segregation, the spindle assembly checkpoint (SAC) delays mitosis exit until mitotic spindle assembly. An exceedingly prolonged mitosis, however, promotes cell death and by this means antimicrotubule cancer drugs (AMCDs), that impair spindle assembly, are believed to kill cancer cells. Despite malformed spindles, cancer cells can, however, slip through SAC, exit mitosis prematurely and resist killing. We show here that the Fcp1 phosphatase and Wee1, the cyclin B-dependent kinase (cdk) 1 inhibitory kinase, play a role for this slippage/resistance mechanism. During AMCD-induced prolonged mitosis, Fcp1-dependent Wee1 reactivation lowered cdk1 activity, weakening SAC-dependent mitotic arrest and leading to mitosis exit and survival. Conversely, genetic or chemical Wee1 inhibition strengthened the SAC, further extended mitosis, reduced antiapoptotic protein Mcl-1 to a minimum and potentiated killing in several, AMCD-treated cancer cell lines and primary human adult lymphoblastic leukemia cells. Thus, the Fcp1-Wee1-Cdk1 (FWC) axis affects SAC robustness and AMCDs sensitivity.

References

Oct 17, 2003·Genes & Development·Vincenzo D'AngiolellaDomenico Grieco
Jan 13, 2006·The New England Journal of Medicine·Ching-Hon Pui, William E Evans
Mar 1, 2007·PloS One·Vincenzo D'AngiolellaDomenico Grieco
Apr 12, 2007·Nature Reviews. Molecular Cell Biology·Andrea Musacchio, Edward D Salmon
Oct 6, 2009·Cancer Cell·Hsiao-Chun HuangTimothy J Mitchison
Jan 17, 2012·Current Biology : CB·Violeta MorinAriane Abrieu
Dec 21, 2012·Cell Cycle·Roberta ViscontiDomenico Grieco
Jul 31, 2013·Current Opinion in Cell Biology·Caroline H Topham, Stephen S Taylor
Sep 10, 2013·Cell Cycle·Khanh DoShivaani Kummar

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Citations

Jun 17, 2016·Molecular & Cellular Oncology·Roberta ViscontiDomenico Grieco
Sep 28, 2016·Journal of Experimental & Clinical Cancer Research : CR·Roberta ViscontiDomenico Grieco
Nov 9, 2017·International Journal of Molecular Sciences·Danî Kalsbeek, Roy M Golsteyn
Aug 16, 2017·Endocrine-related Cancer·Roberta Visconti, Domenico Grieco
Jan 16, 2019·The Journal of Clinical Investigation·Amirali B BukhariArmin M Gamper
Feb 20, 2018·Molecular Cancer·Aniello CerratoAngela Celetti
Jun 16, 2019·Cancers·Angela Flavia SerpicoDomenico Grieco
Oct 12, 2019·FEBS Letters·Adrijana Crncec, Helfrid Hochegger
Feb 13, 2020·F1000Research·Angela Flavia Serpico, Domenico Grieco
Sep 23, 2020·Journal of Hematology & Oncology·Andrea Ghelli Luserna di RoràGiorgia Simonetti
Dec 29, 2015·International Journal of Molecular Medicine·Eva JuengelRoman A Blaheta
Oct 30, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Sadia RahmanElitza P Markova-Car
Jul 17, 2021·Current Oncology Reports·Anthony Kong, Hisham Mehanna

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Methods Mentioned

BETA
transfections
flow cytometry

Software Mentioned

ImageJ

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