The induction of polyploidy or apoptosis by the Aurora A kinase inhibitor MK8745 is p53-dependent
Open Access
- 15 February 2012
- journal article
- Published by Taylor & Francis Ltd in Cell Cycle
- Vol. 11 (4), 807-817
- https://doi.org/10.4161/cc.11.4.19323
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.Keywords
This publication has 30 references indexed in Scilit:
- MK-5108, a Highly Selective Aurora-A Kinase Inhibitor, Shows Antitumor Activity Alone and in Combination with DocetaxelMolecular Cancer Therapeutics, 2010
- Determinants for the efficiency of anticancer drugs targeting either Aurora-A or Aurora-B kinases in human colon carcinoma cellsMolecular Cancer Therapeutics, 2009
- Aurora B Kinase Regulates the Postmitotic Endoreduplication Checkpoint via Phosphorylation of the Retinoblastoma Protein at Serine 780Molecular Biology of the Cell, 2009
- The Topoisomerase I Poison CPT-11 Enhances the Effect of the Aurora B Kinase Inhibitor AZD1152 both In vitro and In vivoClinical Cancer Research, 2009
- Antitumor activity of MLN8054, an orally active small-molecule inhibitor of Aurora A kinaseProceedings of the National Academy of Sciences of the United States of America, 2007
- The Aurora Kinase Inhibitor VX-680 Induces Endoreduplication and Apoptosis Preferentially in Cells with Compromised p53-Dependent Postmitotic Checkpoint FunctionCancer Research, 2006
- The human mitotic checkpoint protein BubR1 regulates chromosome–spindle attachmentsNature, 2004
- Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochoresThe Journal of cell biology, 2003
- The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore–microtubule attachment and in maintaining the spindle assembly checkpointThe Journal of cell biology, 2003
- Human TPX2 is required for targeting Aurora-A kinase to the spindleThe Journal of cell biology, 2002