Abstract
Ovarian cancer is one of the most common cancers among women. Recent studies demonstrated that the gene encoding the p110alpha 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 G(1) cell cycle arrest. This effect was accompanied by the decreased expression of G(1)-associated proteins, including cyclin D1, cyclin-dependent kinase (CDK) 4, CDC25A, and retinoblastoma phosphorylation at Ser(780), Ser(795), and Ser(807/811). Expression of CDK6 and beta-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 G(1) 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 G(1) cell cycle progression and on the expression of cyclin D1, CDK4, CDC25A, and retinoblastoma phosphorylation. These results indicate that PI3K mediates G(1) progression and cyclin expression through activation of an AKT/mTOR/p70S6K1 signaling pathway in the ovarian cancer cells.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Antibiotics, Antineoplastic / pharmacology
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Blood Proteins / pharmacology
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Cell Division / physiology
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Chromones / pharmacology
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Cyclin D1 / metabolism
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinase Inhibitor p16 / metabolism
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Cyclin-Dependent Kinases / metabolism
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Enzyme Inhibitors / pharmacology
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Female
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G1 Phase / drug effects
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G1 Phase / physiology*
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Humans
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Mitogen-Activated Protein Kinases / metabolism
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Morpholines / pharmacology
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Ovarian Neoplasms*
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation
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Protein Kinase Inhibitors
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Protein Kinases / metabolism*
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Protein Serine-Threonine Kinases / metabolism*
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt
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Retinoblastoma Protein / metabolism
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Ribosomal Protein S6 Kinases, 70-kDa / antagonists & inhibitors
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Ribosomal Protein S6 Kinases, 70-kDa / metabolism*
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Sirolimus / pharmacology
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TOR Serine-Threonine Kinases
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Tumor Cells, Cultured
Substances
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Antibiotics, Antineoplastic
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Blood Proteins
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Chromones
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Cyclin-Dependent Kinase Inhibitor p16
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Enzyme Inhibitors
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Retinoblastoma Protein
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Cyclin D1
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Protein Kinases
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MTOR protein, human
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Ribosomal Protein S6 Kinases, 70-kDa
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TOR Serine-Threonine Kinases
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CDK4 protein, human
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinases
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Mitogen-Activated Protein Kinases
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Sirolimus