The Fcp1-Wee1-Cdk1 axis affects spindle assembly checkpoint robustness and sensitivity to antimicrotubule cancer drugs.
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.
1] CEINGE Biotecnologie Avanzate, Gaetano Salvatore 486, Naples 80145, Italy [2] IEOS, CNR, S. Pansini 5, Naples 80131, Italy.
R
R
Visconti
1] CEINGE Biotecnologie Avanzate, Gaetano Salvatore 486, Naples 80145, Italy [2] DMMBM, University of Naples "Federico II", S. Pansini 5, Naples 80131, Italy.
R
R
Della Monica
Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
L
L
Palazzo
CEINGE Biotecnologie Avanzate, Gaetano Salvatore 486, Naples 80145, Italy.
F
F
D'Alessio
CEINGE Biotecnologie Avanzate, Gaetano Salvatore 486, Naples 80145, Italy.
M
M
Raia
Division of Hematology, PO San Gennaro, ASL-NA1 Centro, Naples 80136, Italy.
S
S
Improta
Division of Hematology, PO San Gennaro, ASL-NA1 Centro, Naples 80136, Italy.
M R
MR
Villa
1] CEINGE Biotecnologie Avanzate, Gaetano Salvatore 486, Naples 80145, Italy [2] DMMBM, University of Naples "Federico II", S. Pansini 5, Naples 80131, Italy.
L
L
Del Vecchio
1] CEINGE Biotecnologie Avanzate, Gaetano Salvatore 486, Naples 80145, Italy [2] DMMBM, University of Naples "Federico II", S. Pansini 5, Naples 80131, Italy.
D
D
Grieco
D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016203:CDC2 Protein Kinase; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D008870:Microtubules / Q000187:drug effects*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D008941:Spindle Apparatus / Q000187:drug effects* / Q000378:metabolism*; D055815:Young Adult
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; C000588909:Fcp1 protein, human; D010749:Phosphoprotein Phosphatases