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Am J Physiol Cell Physiol (March 17, 2004). doi:10.1152/ajpcell.00422.2003
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Submitted on October 2, 2003
Accepted on March 15, 2004

The G1 cell cycle progression and the expression of G1 cyclins are regulated by PI3K/AKT/mTOR/p70S6K1 signaling in human ovarian cancer cells

Ning Gao1, Daniel C Flynn1, Zhuo Zhang2, Xiao-Song Zhong1, Valerie Walker1, Ke J Liu3, Xianglin Shi2, and Bing-Hua Jiang1*

1 MBR Cancer Center, Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, WV, USA
2 Health Effects Lab, NIOSH, Morgantown, WV, USA
3 Pharmacy, University of New Mexico, Albuquerque, NM, USA

* To whom correspondence should be addressed. E-mail: bhjiang{at}hsc.wvu.edu.

Ovarian cancer is one of the most common cancers among women. Recent studies demonstrated that the gene encoding the p110{alpha} catalytic subunit of phosphatidylinositol 3-kinase (PI3K) is frequently amplified in ovarian cancer cells. PI3K is involved in multiple cellular functions including proliferation, differentiation, anti-apoptosis, tumorigenesis, and angiogenesis. In this study, we demonstrate that the inhibition of PI3K activity by LY294002 inhibited ovarian cancer cell proliferation and induced G1 cell cycle arrest. This effect was accompanied by the decreased expression of G1-associated proteins including cyclin D1, CDK4, CDC25A, and Rb phosphorylation at Ser780, Ser795, and Ser807/811. Expression of CDK6 and {beta}-actin was not affected by LY294002. Expression of the cyclin kinase inhibitor p16INK4a was induced by the PI3K inhibitor, while steady state levels of p21CIP1/WAF1 were decreased in the same experiment. The inhibition of PI3K activity also inhibited the phosphorylation of AKT and p70S6K1, but not ERK1/2. The G1 cell cycle arrest induced by LY294002 was restored by the expression of active forms of AKT and p70S6K1 in the cells. Our study shows that PI3K transmits a mitogenic signal through AKT and mTOR to p70S6K1. The mTOR inhibitor rapamycin had similar inhibitory effects on G1 cell cycle progression and expression of cyclin D1, CDK4, CDC25A, and Rb phosphorylation. These results indicate that PI3K mediates G1 progression and cyclin expression through activation of AKT/mTOR/p70S6K1 signaling pathway in the ovarian cancer cells.




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