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

Cell Cycle. 2012 Feb 15;11(4):807-17. doi: 10.4161/cc.11.4.19323. Epub 2012 Feb 15.

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.

MeSH terms

  • Apoptosis / drug effects*
  • Aurora Kinases
  • Cell Cycle / drug effects
  • Cell Cycle / 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
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Protein Kinase Inhibitors
  • Tumor Suppressor Protein p53
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases