Document Detail


The induction of polyploidy or apoptosis by the Aurora A kinase inhibitor MK8745 is p53-dependent.
MedLine Citation:
PMID:  22293494     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Aurora kinases are mitotic serine/threonine protein kinases and are attractive novel targets for anticancer therapy. Many small-molecule inhibitors of Aurora kinases are currently undergoing clinical trials. Aurora A kinase is essential for successful mitotic transition. MK8745 is a novel and selective small-molecule inhibitor of Aurora A kinase. MK8745 induced apoptotic cell death in a p53-dependent manner when tested in vitro in cell lines of multiple lineages. Cells expressing wild-type p53 showed a short delay in mitosis followed by cytokinesis, resulting in 2N cells along with apoptosis. However, cells lacking or with mutant p53 resulted in a prolonged arrest in mitosis followed by endoreduplication and polyploidy. Cytokinesis was completely inhibited in p53-deficient cells, as observed by the absence of 2N cell population. The induction of apoptosis in p53-proficient cells was associated with activation of caspase 3 and release of cytochrome c but was independent of p21. Exposure of p53 wild-type cells to MK8745 resulted in the induction of p53 phosphorylation (ser15) and an increase in p53 protein expression. p53-dependent apoptosis by MK8745 was further confirmed in HCT 116 p53(-/-) cells transfected with wild-type p53. Transient knockdown of Aurora A by specific siRNA recapitulated these p53- dependent effects, with greater percent induction of apoptosis in p53 wild-type cells. In conclusion, our studies show p53 as a determining factor for induction of apoptosis vs. polyploidy upon inhibition of Aurora A.
Authors:
Jayasree S Nair; Alan L Ho; Gary K Schwartz
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Publication Detail:
Type:  Journal Article     Date:  2012-02-15
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  11     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-02-29     Completed Date:  2012-09-14     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  807-17     Citation Subset:  IM    
Affiliation:
Laboratory of New Drug Development, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. nairj@mskcc.org
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MeSH Terms
Descriptor/Qualifier:
Apoptosis / drug effects*
Cell Cycle / drug effects,  genetics
Cell Proliferation / drug effects
Flow Cytometry
Fluorescent Antibody Technique
HCT116 Cells
Humans
Microscopy, Fluorescence
Polyploidy*
Protein Kinase Inhibitors / pharmacology*
Protein-Serine-Threonine Kinases / antagonists & inhibitors*
Tumor Suppressor Protein p53 / genetics,  metabolism*
Chemical
Reg. No./Substance:
0/Protein Kinase Inhibitors; 0/Tumor Suppressor Protein p53; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/aurora kinase
Comments/Corrections

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