Abstract
Vascular endothelial growth factor (VEGF) expression is elevated in ovarian and other cancer cells. However, the mechanism that causes the increase in VEGF expression still remains to be elucidated. In this study, we demonstrated that activation of PI3K signaling mediated VEGF protein expression at the transcriptional level through hypoxia-inducible factor 1alpha (HIF-1alpha) expression in human ovarian cancer cells. We found that inhibition of PI3K activity by LY294002 decreased VEGF transcriptional activation and that forced expression of AKT completely reversed the inhibitory effect. HDM2 and p70S6K1 are two downstream targets of AKT that mediate growth factor-induced VEGF transcriptional activation and HIF-1alpha expression. The inhibition of PI3K by LY294002 inhibited p70S6K1 and HDM2 activity in the cells. Forced expression of p70S6K1 or HDM2 reversed LY294002-inhibited VEGF transcriptional activation and HIF-1alpha expression. This study identifies a potential novel mechanism responsible for increased VEGF expression in ovarian cancer cells. It also indicates the important role of VEGF and HIF-1 in ovarian tumorigenesis and angiogenesis, which is mediated by the PI3K/AKT/HDM2 and AKT/p70S6K1 pathways in 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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Cell Line, Tumor
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Chromones / pharmacology
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DNA-Binding Proteins / physiology*
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Female
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Humans
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Morpholines / pharmacology
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Nuclear Proteins / physiology*
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Ovarian Neoplasms / etiology
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Ovarian Neoplasms / metabolism*
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Phosphatidylinositol 3-Kinases / physiology*
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Phosphorylation
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Protein Serine-Threonine Kinases / physiology*
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Proto-Oncogene Proteins / physiology*
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-mdm2
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Ribosomal Protein S6 Kinases, 70-kDa / physiology*
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Signal Transduction*
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Sirolimus / pharmacology
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Transcription Factors / physiology*
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Transcriptional Activation*
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Vascular Endothelial Growth Factor A / genetics*
Substances
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Chromones
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DNA-Binding Proteins
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HIF1A protein, human
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Morpholines
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Nuclear Proteins
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Proto-Oncogene Proteins
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Transcription Factors
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Vascular Endothelial Growth Factor A
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2
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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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Sirolimus