Akt Inhibitor A-443654 Interferes with Mitotic Progression by Regulating Aurora A Kinase Expression
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 G2/M accumulation, defects in centroso...
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doaj-f6c80b51bea0494ca302ce26868e72452020-11-24T23:15:28ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022008-08-0110882883710.1593/neo.08408Akt Inhibitor A-443654 Interferes with Mitotic Progression by Regulating Aurora A Kinase ExpressionXuesong Liu0Yan Shi1Keith W. Woods2Paul Hessler3Paul Kroeger4Julie Wilsbacher5Jieyi Wang6Jean Y. Wang7Chunying Li8Qun Li9Saul H. Rosenberg10Vincent L. Giranda11Yan Luo12Department of R47S, GPRD, Abbott Laboratories, Abbott Park, IL 60064, USADepartment of R47S, GPRD, Abbott Laboratories, Abbott Park, IL 60064, USADepartment of R47S, GPRD, Abbott Laboratories, Abbott Park, IL 60064, USADepartment of R4CT, GPRD, Abbott Laboratories, Abbott Park, IL 60064, USADepartment of R4CT, GPRD, Abbott Laboratories, Abbott Park, IL 60064, USADepartment of R47A, GPRD, Abbott Laboratories, Abbott Park, IL 60064, USADepartment of R47A, GPRD, Abbott Laboratories, Abbott Park, IL 60064, USAMoores UCSD Cancer Center, UCSD School of Medicine, 3855 Health Sciences Drive, CA 92093, USADepartment of Pharmacology, University of California, Irvine, CA 92697, USADepartment of R47S, GPRD, Abbott Laboratories, Abbott Park, IL 60064, USADepartment of R460, GPRD, Abbott Laboratories, Abbott Park, IL 60064, USADepartment of R47S, GPRD, Abbott Laboratories, Abbott Park, IL 60064, USADepartment of R47S, GPRD, Abbott Laboratories, Abbott Park, IL 60064, USA 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 G2/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. http://www.sciencedirect.com/science/article/pii/S147655860880036X |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Xuesong Liu Yan Shi Keith W. Woods Paul Hessler Paul Kroeger Julie Wilsbacher Jieyi Wang Jean Y. Wang Chunying Li Qun Li Saul H. Rosenberg Vincent L. Giranda Yan Luo |
spellingShingle |
Xuesong Liu Yan Shi Keith W. Woods Paul Hessler Paul Kroeger Julie Wilsbacher Jieyi Wang Jean Y. Wang Chunying Li Qun Li Saul H. Rosenberg Vincent L. Giranda Yan Luo Akt Inhibitor A-443654 Interferes with Mitotic Progression by Regulating Aurora A Kinase Expression Neoplasia: An International Journal for Oncology Research |
author_facet |
Xuesong Liu Yan Shi Keith W. Woods Paul Hessler Paul Kroeger Julie Wilsbacher Jieyi Wang Jean Y. Wang Chunying Li Qun Li Saul H. Rosenberg Vincent L. Giranda Yan Luo |
author_sort |
Xuesong Liu |
title |
Akt Inhibitor A-443654 Interferes with Mitotic Progression by Regulating Aurora A Kinase Expression |
title_short |
Akt Inhibitor A-443654 Interferes with Mitotic Progression by Regulating Aurora A Kinase Expression |
title_full |
Akt Inhibitor A-443654 Interferes with Mitotic Progression by Regulating Aurora A Kinase Expression |
title_fullStr |
Akt Inhibitor A-443654 Interferes with Mitotic Progression by Regulating Aurora A Kinase Expression |
title_full_unstemmed |
Akt Inhibitor A-443654 Interferes with Mitotic Progression by Regulating Aurora A Kinase Expression |
title_sort |
akt inhibitor a-443654 interferes with mitotic progression by regulating aurora a kinase expression |
publisher |
Elsevier |
series |
Neoplasia: An International Journal for Oncology Research |
issn |
1476-5586 1522-8002 |
publishDate |
2008-08-01 |
description |
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 G2/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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url |
http://www.sciencedirect.com/science/article/pii/S147655860880036X |
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