Abstract
Arsenite is widely distributed environmental toxicant in water, food and air. It is a known human carcinogen, which is strongly associated with human cancers originated from liver, nasal cavity, lung, skin, bladder, kidney, and prostate. In this study, we investigated whether arsenite induces expression of hypoxia-inducible factor 1 (HIF-1). HIF-1 is a heterodimeric basic helix-loop-helix transcription factor, composed of HIF-1alpha and HIF-1beta/ARNT subunits; and is involved in tumor growth and angiogenesis. Here we demonstrate that arsenite induces the expression of HIF-1alpha but not HIF-1beta subunit in DU145 human prostate carcinoma cells. Arsenite also increases the expression of VEGF through the induction of HIF-1. We also found that arsenite activates PI3K and Akt that are required for arsenite-induced expression of HIF-1alpha and VEGF. The induction of HIF-1 and VEGF by arsenite can not be inhibited by MAP kinase inhibitors. Arsenite causes production of reactive oxygen species (ROS). The major species of ROS required for the induction of HIF-1 and VEGF is H2O2. These data indicate that the arsenite-induced activation of PI3K/Akt signaling and the expression of HIF-1 and VEGF through the generation of ROS could be an important mechanism in the arsenite-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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Androstadienes / pharmacology
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Arsenites / pharmacology*
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Cell Line, Tumor
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Chromones / pharmacology
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DNA-Binding Proteins / biosynthesis*
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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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Male
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Morpholines / pharmacology
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Nuclear Proteins / biosynthesis*
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation / drug effects
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Prostatic Neoplasms / 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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Reactive Oxygen Species / metabolism*
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Signal Transduction / drug effects
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Teratogens / pharmacology*
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Transcription Factors*
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Vascular Endothelial Growth Factor A / biosynthesis*
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Wortmannin
Substances
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Androstadienes
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Arsenites
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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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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins
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Reactive Oxygen Species
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Teratogens
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Transcription Factors
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VEGFA protein, human
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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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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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arsenite
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Wortmannin