Abstract
Ovarian cancer has the highest mortality rate of any gynecological disease affecting women in Western countries. VEGF is a crucial inducer of angiogenesis both in vivo and in vitro. VEGF is commonly upregulated in ovarian cancer and is regulated by HIF-1. SU5416 is known to inhibit various stages of tumor growth. In this study, we show that SU5416 inhibited VEGF mRNA expression in ovarian cancer cells in a dose-dependent manner. SU5416 inhibited VEGF expression at the transcriptional level through the HIF-1 DNA binding site. HIF-1 is composed of HIF-1alpha and HIF-1beta subunits. SU5416 specifically decreased HIF-1alpha, but not HIF-1beta protein levels. To understand the signaling pathways regulating SU5416-inhibited VEGF and HIF-1alpha expression, we found that SU5416 inhibited PI3K activity. AKT is a downstream target of PI3K. We found that SU5416 also inhibited AKT and p70S6K1 activation and activity in a dose-dependent manner. These results demonstrate that SU5416 inhibited VEGF and HIF-1alpha expression through the inhibition of PI3K/AKT/p70S6K1 pathway in ovarian cancer cells. These results indicate that SU5416 may be an effective agent for ovarian cancer treatment through the inhibition of VEGF and HIF-1 expression, and the activation of PI3K/AKT/p70S6K1 signaling pathway.
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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Binding Sites
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Blotting, Northern
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Cell Line, Tumor
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Cell Proliferation
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / pharmacology
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Female
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit
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Immunoblotting
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Indoles / pharmacology*
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Luciferases / metabolism
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Neovascularization, Pathologic*
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Ovarian Neoplasms / drug therapy
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Ovarian Neoplasms / enzymology
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Ovarian Neoplasms / metabolism
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphorylation
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Plasmids / metabolism
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Protein Binding
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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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Pyrroles / pharmacology*
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RNA / metabolism
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RNA, Messenger / metabolism
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Ribosomal Protein S6 Kinases, 70-kDa / metabolism*
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Signal Transduction
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Tetrazolium Salts / pharmacology
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Thiazoles / pharmacology
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Time Factors
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Transcription Factors / antagonists & inhibitors*
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Transcriptional Activation
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Transfection
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Up-Regulation
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Vascular Endothelial Growth Factor A / antagonists & inhibitors*
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Vascular Endothelial Growth Factor A / metabolism
Substances
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Enzyme Inhibitors
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Indoles
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Proto-Oncogene Proteins
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Pyrroles
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RNA, Messenger
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Tetrazolium Salts
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Thiazoles
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Transcription Factors
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Vascular Endothelial Growth Factor A
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RNA
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Semaxinib
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Luciferases
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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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thiazolyl blue