Induction of Vascular Endothelial Growth Factor Expression and Hypoxia-inducible Factor 1α Protein by the Oxidative Stressor Arsenite
Recent evidence suggests that vascular endothelial growth factor ( VEGF ) expression is up-regulated by oxidative stressors through activation of hypoxia-inducible Factor 1 (HIF-1). To investigate whether this is a general phenomenon, we studied the effects of the sulfhydryl reagent arsenite on VEGF...
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Veröffentlicht in: | The Journal of biological chemistry 2001-12, Vol.276 (51), p.48066 |
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Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | Recent evidence suggests that vascular endothelial growth factor ( VEGF ) expression is up-regulated by oxidative stressors through activation of hypoxia-inducible Factor 1 (HIF-1). To investigate
whether this is a general phenomenon, we studied the effects of the sulfhydryl reagent arsenite on VEGF expression in human
ovarian cancer cells. Arsenite potently induces the production of reactive oxygen species (ROS) in several cell systems and
directly interacts with sulfhydryl groups of cellular thiols. We report that arsenite induces VEGF mRNA and protein levels
in normoxic H134 and OVCAR-3 cells. Arsenite also increases HIF-1α protein levels, suggesting a role for HIF-1 in the induction
of VEGF expression. Pretreatment with the ROS inhibitors catalase and mannitol attenuated arsenite-induced ROS production, but did
not affect induction of VEGF mRNA and HIF-1α protein. In contrast, pretreatment with the thiol antioxidants glutathione or N -acetylcysteine completely abrogated both effects, whereas a potentiation was observed by depletion of intracellular glutathione.
These results demonstrate that arsenite-induced VEGF mRNA and HIF-1α protein expression is independent of increased ROS production
but critically regulated by the cellular reduced glutathione content. In addition, these data suggest the involvement of a
thiol-sensitive mechanism in the regulation of VEGF mRNA expression and HIF-1α protein in human ovarian cancer cells. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M106282200 |