The induction of polyploidy or apoptosis by the Aurora A kinase inhibitor MK8745 is p53-dependent Journal Article

   

Authors:	Nair, J. S.; Ho, A. L.; Schwartz, G. K.
Article Title:	The induction of polyploidy or apoptosis by the Aurora A kinase inhibitor MK8745 is p53-dependent
Abstract:	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. © 2012 Landes Bioscience.
Keywords:	controlled study; human tissue; protein expression; protein phosphorylation; unclassified drug; human cell; flow cytometry; cell proliferation; cell cycle; apoptosis; protein kinase inhibitor; cell line; small interfering rna; hct116 cells; caspase 3; cancer cell culture; drug structure; enzyme activation; in vitro study; protein p53; protein kinase inhibitors; fluorescent antibody technique; genetic transfection; protein-serine-threonine kinases; tumor suppressor protein p53; microscopy, fluorescence; gene silencing; colon carcinoma; protein p21; polyploidy; p53; cytokinesis; aurora a kinase; cytochrome c; aurora a kinase inhibitor; mk 8745
Journal Title:	Cell Cycle
Volume:	11
Issue:	4
ISSN:	1538-4101
Publisher:	Taylor & Francis Inc.
Date Published:	2012-02-15
Start Page:	807
End Page:	817
Language:	English
DOI:	10.4161/cc.11.4.19323
PROVIDER:	scopus
PMCID:	PMC3318110
PUBMED:	22293494
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84857466069&partnerID=40&md5=1ca82e4d74f227724c23aa340259702f
Notes:	--- - "Export Date: 2 April 2012" - "Source: Scopus"

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