Vanadate-induced expression of hypoxia-inducible factor 1alpha and vascular endothelial growth factor through phosphatidylinositol 3-kinase/Akt pathway and reactive oxygen species.
Gao-N; Ding-M; Zheng-JZ; Zhang-Z; Leonard-SS; Liu-KJ; Shi-X; Jiang-BH
J Biol Chem 2002 Aug; 277(30):31963-31971
Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix transcription factor composed of HIF-1alpha and HIF-1 beta/aryl hydrocarbon nuclear translocator subunits. HIF-1 expression is induced by hypoxia, growth factors, and activation of oncogenes. In response to hypoxia, HIF-1 activates the expression of many genes including vascular endothelial growth factor (VEGF) and erythropoietin. HIF-1 and VEGF play an important role in angiogenesis and tumor progression. Vanadate is widely used in industry, and is a potent inducer of tumors in humans and animals. In this study, we demonstrate that vanadate induces HIF-1 activity through the expression of HIF-1alpha but not HIF-1beta subunit, and increases VEGF expression in DU145 human prostate carcinoma cells. We also studied the signaling pathway involved in vanadate-induced HIF-1 alpha and VEGF expression and found that phosphatidylinositol 3-kinase/Akt signaling was required for HIF-1 and VEGF expression induced by vanadate, whereas mitogen-activated protein kinase pathway was not required. We also found that reactive oxygen species (ROS) were involved in vanadate-induced expression of HIF-1 and VEGF in DU145 cells. The major species of ROS responsible for the induction of HIF-1 and VEGF expression was H2O2. These results suggest that the expression of HIF-1 and VEGF induced by vanadate through PI3K/Akt may be an important signaling pathway in the vanadate-induced carcinogenesis, and ROS may play an important role.
Cancer; Carcinogens; Carcinomas; Cell-biology; Cell-growth; Cellular-function; Chemical-kinetics; Chemical-properties; Chemical-reactions; Humans; Tumors; Hypoxia; Mutation; Gene-mutation; Genes; Genotoxic-effects; Biochemical-analysis; Biochemical-tests; Biochemistry; Vanadium-compounds;
Mary Babb Randolph Cancer Center, Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, West Virginia 26506-9300, USA
Research Tools and Approaches: Cancer Research Methods
Journal of Biological Chemistry