Abstract
Chromium(VI) (Cr(VI)) is widely used in industry and is a potent inducer of tumors in animals. The present study demonstrates that Cr(VI) induces hypoxia-inducible factor 1 (HIF-1) activity through the specific expression of HIF-1alpha but not HIF-1beta subunit and increases the level of vascular endothelial growth factor (VEGF) expression in DU145 human prostate carcinoma cells. To dissect the signaling pathways involved in Cr(VI)-induced HIF-1 expression, we found that p38 mitogen-activated protein kinase signaling was required for HIF-1alpha expression induced by Cr(VI). Neither phosphatidylinositol 3-kinase nor extracellular signal-regulated kinase activity was required for Cr(VI)-induced HIF-1 expression. Cr(VI) induced expression of HIF-1 and VEGF through the production of reactive oxygen species in DU145 cells. The major species of reactive oxygen species responsible for the induction of HIF-1 and VEGF expression is H(2)O(2). These results suggest that the expression of HIF-1 and VEGF induced by Cr(VI) may be an important signaling pathway in the Cr(VI)-induced carcinogenesis.
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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Antioxidants / metabolism
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Carcinoma
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Catalase / metabolism
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Chromium / metabolism*
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Electron Spin Resonance Spectroscopy
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Endothelial Growth Factors / genetics
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Endothelial Growth Factors / metabolism*
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Enzyme Inhibitors / metabolism
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Flow Cytometry
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Gene Expression Regulation*
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Humans
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Hydrogen Peroxide / metabolism
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Hypoxia-Inducible Factor 1, alpha Subunit
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism*
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Lymphokines / genetics
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Lymphokines / metabolism*
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Male
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Mitogen-Activated Protein Kinases / metabolism*
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Oxidants / metabolism
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Oxygen / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Prostatic Neoplasms
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Reactive Oxygen Species / metabolism
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Signal Transduction / physiology*
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Transcription Factors / metabolism*
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Transcription, Genetic
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Tumor Cells, Cultured
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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p38 Mitogen-Activated Protein Kinases
Substances
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Antioxidants
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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, alpha Subunit
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Intercellular Signaling Peptides and Proteins
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Lymphokines
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Oxidants
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Reactive Oxygen Species
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Transcription Factors
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Chromium
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chromium hexavalent ion
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Hydrogen Peroxide
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Catalase
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Phosphatidylinositol 3-Kinases
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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Oxygen