Vanadate-induced expression of hypoxia-inducible factor 1 alpha and vascular endothelial growth factor through phosphatidylinositol 3-kinase/Akt pathway and reactive oxygen species.

Abstract

Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix transcription factor composed of HIF-1 alpha 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-1 beta 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 H(2)O(2). 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.

• Authors: Ning Gao, Min Ding, Jenny Z Zheng, Zhuo Zhang, Stephen S Leonard, Ke Jian Liu, Xianglin Shi, Bing-Hua Jiang
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 277 Issue 35 Pg. 31963-71 (Aug 30 2002) ISSN: 0021-9258 [Print] United States
• PMID: 12070140 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antioxidants
• Endothelial Growth Factors
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Lymphokines
• Proto-Oncogene Proteins
• Reactive Oxygen Species
• Transcription Factors
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors
• Vanadates
• Protein-Tyrosine Kinases
• AKT1 protein, human
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• MAP Kinase Kinase Kinase 1
• MAP3K1 protein, human

Topics

• Antioxidants (pharmacology)
• Endothelial Growth Factors (genetics)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit
• Kinetics
• Lymphokines (genetics)
• MAP Kinase Kinase Kinase 1
• Male
• Phosphatidylinositol 3-Kinases (metabolism)
• Prostatic Neoplasms
• Protein Serine-Threonine Kinases (metabolism)
• Protein-Tyrosine Kinases (metabolism)
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-akt
• Reactive Oxygen Species (metabolism)
• Transcription Factors (drug effects, genetics)
• Tumor Cells, Cultured
• Vanadates (pharmacology)
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors