Abstract
Dysregulated signal transduction from receptor tyrosine kinases to phosphatidylinositol 3-kinase (PI3K), AKT (protein kinase B), and its effector FKBP-rapamycin-associated protein (FRAP) occurs via autocrine stimulation or inactivation of the tumor suppressor PTEN in many cancers. Here we demonstrate that in human prostate cancer cells, basal-, growth factor-, and mitogen-induced expression of hypoxia-inducible factor 1 (HIF-1) alpha, the regulated subunit of the transcription factor HIF-1, is blocked by LY294002 and rapamycin, inhibitors of PI3K and FRAP, respectively. HIF-1-dependent gene transcription is blocked by dominant-negative AKT or PI3K and by wild-type PTEN, whereas transcription is stimulated by constitutively active AKT or dominant-negative PTEN. LY294002 and rapamycin also inhibit growth factor- and mitogen-induced secretion of vascular endothelial growth factor, the product of a known HIF-1 target gene, thus linking the PI3K/PTEN/AKT/FRAP pathway, HIF-1, and tumor angiogenesis. These data indicate that pharmacological agents that target PI3K, AKT, or FRAP in tumor cells inhibit HIF-1alpha expression and that such inhibition may contribute to therapeutic efficacy.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Carrier Proteins*
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Chromones / pharmacology
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Culture Media, Serum-Free / pharmacology
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DNA-Binding Proteins / biosynthesis*
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DNA-Binding Proteins / drug effects
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Endothelial Growth Factors / biosynthesis
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Endothelial Growth Factors / pharmacology
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Enzyme Inhibitors / pharmacology
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Enzyme-Linked Immunosorbent Assay
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Epidermal Growth Factor / genetics
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Epidermal Growth Factor / pharmacology
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Epidermal Growth Factor / physiology
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Humans
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Hypoxia / physiopathology
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Immunophilins / genetics
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Immunophilins / physiology
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Lymphokines / biosynthesis
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Lymphokines / pharmacology
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Male
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Morpholines / pharmacology
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Neovascularization, Pathologic / metabolism
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Nuclear Proteins / biosynthesis*
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Nuclear Proteins / drug effects
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PTEN Phosphohydrolase
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / physiology
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Phosphoinositide-3 Kinase Inhibitors
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Phosphoric Monoester Hydrolases / genetics
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Phosphoric Monoester Hydrolases / physiology
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Phosphotransferases (Alcohol Group Acceptor)*
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Prostatic Neoplasms / drug therapy
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Prostatic Neoplasms / metabolism*
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Prostatic Neoplasms / pathology
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / physiology
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Proto-Oncogene Proteins c-akt
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Signal Transduction / physiology*
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TOR Serine-Threonine Kinases
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Tetradecanoylphorbol Acetate / pharmacology
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Transcription Factors*
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / metabolism
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Tumor Suppressor Proteins*
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
Substances
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Carrier Proteins
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Chromones
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Culture Media, Serum-Free
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DNA-Binding Proteins
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Endothelial Growth Factors
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Enzyme Inhibitors
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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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Lymphokines
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Morpholines
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Nuclear Proteins
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins
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Transcription Factors
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Tumor Suppressor Proteins
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Epidermal Growth Factor
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Phosphotransferases (Alcohol Group Acceptor)
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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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TOR Serine-Threonine Kinases
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Phosphoric Monoester Hydrolases
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PTEN Phosphohydrolase
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PTEN protein, human
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Immunophilins
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Tetradecanoylphorbol Acetate