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RECEPTORS AND SIGNAL TRANSDUCTION

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

¹Mary Babb Randolph Cancer Center, Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown 26506-9300; ²Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505; and ³College of Pharmacy, University of New Mexico, Albuquerque, New Mexico 87131

Submitted 2 October 2003 ; accepted in final form 15 March 2004

Ovarian cancer is one of the most common cancers among women. Recent studies demonstrated that the gene encoding the p110 catalytic subunit of phosphatidylinositol 3-kinase (PI3K) is frequently amplified in ovarian cancer cells. PI3K is involved in multiple cellular functions, including proliferation, differentiation, antiapoptosis, tumorigenesis, and angiogenesis. In this study, we demonstrate that the inhibition of PI3K activity by LY-294002 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, cyclin-dependent kinase (CDK) 4, CDC25A, and retinoblastoma phosphorylation at Ser⁷⁸⁰, Ser⁷⁹⁵, and Ser^807/811. Expression of CDK6 and -actin was not affected by LY-294002. Expression of the cyclin kinase inhibitor p16^INK4a was induced by the PI3K inhibitor, whereas steady-state levels of p21^CIP1/WAF1 were decreased in the same experiment. The inhibition of PI3K activity also inhibited the phosphorylation of AKT and p70S6K1, but not extracellular regulated kinase 1/2. The G₁ cell cycle arrest induced by LY-294002 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 mammalian target of rapamycin (mTOR) to p70S6K1. The mTOR inhibitor rapamycin had similar inhibitory effects on G₁ cell cycle progression and on the expression of cyclin D1, CDK4, CDC25A, and retinoblastoma phosphorylation. These results indicate that PI3K mediates G₁ progression and cyclin expression through activation of an AKT/mTOR/p70S6K1 signaling pathway in the ovarian cancer cells.

phosphatidylinositol 3-kinase; cyclin-dependent kinases; retinoblastoma protein

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