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 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.
Liu
Xuesong
X
Department of R47S, GPRD, Abbott Laboratories, Abbott Park, IL 60064, USA. xuesong.liu@abbott.com
Shi
Yan
Y
Woods
Keith W
KW
Hessler
Paul
P
Kroeger
Paul
P
Wilsbacher
Julie
J
Wang
Jieyi
J
Wang
Jean Y
JY
Li
Chunying
C
Li
Qun
Q
Rosenberg
Saul H
SH
Giranda
Vincent L
VL
Luo
Yan
Y
D064127:Aurora Kinases; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D018385:Centrosome / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007191:Indazoles / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008938:Mitosis / Q000187:drug effects*; D015394:Molecular Structure; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D008941:Spindle Apparatus / Q000187:drug effects / Q000378:metabolism; D013237:Stereoisomerism
C504035:A 443654; D007191:Indazoles; D007211:Indoles; D012333:RNA, Messenger; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt