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Many oncogenes induce expression of vascular endothelial growth factor (VEGF), a key factor in tumor angiogenesis. Phosphatidylinositol 3'-kinase (PI3K)/Akt is a common signaling pathway for oncogenes and tumor suppressor genes and is involved in VEGF regulation. Because hypoxia is a major stimulus for VEGF production, we examined the effects of LY294002, a selective PI3K inhibitor, on hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha expression and on endogenous VEGF responses to hypoxia. A panel of breast cancer cell lines reflecting the different genetic changes occurring in human breast cancer was analyzed. LY294002 inhibited HIF-1alpha induction and phosphorylation under hypoxia. However, HIF-2alpha expression was not affected. Basal and hypoxia-inducible VEGF expression was reduced at both mRNA and protein levels by 50%. V12-ras overexpression resulted in an increase in hypoxia-induced HIF-1alpha and HIF-2alpha expression. This effect was blocked by PI3K inhibitor, demonstrating one mechanism for ras synergy with hypoxia-mediated induction of genes. The decreased HIF-1alpha expression was not dependent on VHL interaction because a renal carcinoma cell line with VHL mutation and constitutive high HIF-1alpha expression also showed down-regulation of HIF-1alpha after treatment with LY294002. These results have implications for the use of PI3K inhibitors to inhibit synergistic effects of hypoxia with a wide range of common oncogenes.

Type

Journal article

Journal

Cancer Res

Publication Date

01/10/2001

Volume

61

Pages

7349 - 7355

Keywords

Basic Helix-Loop-Helix Transcription Factors, Blotting, Western, Breast Neoplasms, Carcinoma, Renal Cell, Cell Hypoxia, Chromones, DNA-Binding Proteins, Endothelial Growth Factors, Enzyme Inhibitors, Gene Expression Regulation, Neoplastic, Humans, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, Kidney Neoplasms, Ligases, Lymphokines, Morpholines, Mutation, Nuclear Proteins, PTEN Phosphohydrolase, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Phosphoric Monoester Hydrolases, Protein-Serine-Threonine Kinases, Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, RNA, Messenger, Signal Transduction, Trans-Activators, Transcription Factors, Tumor Cells, Cultured, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Ubiquitins, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors, Von Hippel-Lindau Tumor Suppressor Protein, ras Proteins