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Akt inhibitor a-443654 interferes with mitotic progression by regulating aurora a kinase expression.

Authors
  • Liu, Xuesong
  • Shi, Yan
  • Woods, Keith W
  • Hessler, Paul
  • Kroeger, Paul
  • Wilsbacher, Julie
  • Wang, Jieyi
  • Wang, Jean Y
  • Li, Chunying
  • Li, Qun
  • Rosenberg, Saul H
  • Giranda, Vincent L
  • Luo, Yan
Type
Published Article
Journal
Neoplasia
Publisher
Elsevier
Publication Date
Aug 01, 2008
Volume
10
Issue
8
Pages
828–837
Identifiers
PMID: 18670641
Source
Medline
License
Unknown

Abstract

Both Akt and Aurora A kinase have been shown to be important targets for intervention for cancer therapy. We report here that Compound A (A-443654), a specific Akt inhibitor, interferes with mitotic progression and bipolar spindle formation. Compound A induces G(2)/M accumulation, defects in centrosome separation, and formation of either monopolar arrays or disorganized spindles. On the basis of gene expression array studies, we identified Aurora A as one of the genes regulated transcriptionally by Akt inhibitors including Compound A. Inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, either by PI3K inhibitor LY294002 or by Compound A, dramatically inhibits the promoter activity of Aurora A, whereas the mammalian target of rapamycin inhibitor has little effect, suggesting that Akt might be responsible for up-regulating Aurora A for mitotic progression. Further analysis of the Aurora A promoter region indicates that the Ets element but not the Sp1 element is required for Compound A-sensitive transcriptional control of Aurora A. Overexpression of Aurora A in cells treated with Compound A attenuates the mitotic arrest and the defects in bipolar spindle formation induced by Akt inhibition. Our studies suggest that that Akt may promote mitotic progression through the transcriptional regulation of Aurora A.

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