Effects of ras and von Hippel-Lindau (VHL) gene mutations on hypoxia-inducible factor (HIF)-1alpha, HIF-2alpha, and vascular endothelial growth factor expression and their regulation by the phosphatidylinositol 3'-kinase/Akt signaling pathway. Cancer research. [Cancer Res] Journal article

Title	Effects of ras and von Hippel-Lindau (VHL) gene mutations on hypoxia-inducible factor (HIF)-1alpha, HIF-2alpha, and vascular endothelial growth factor expression and their regulation by the phosphatidylinositol 3'-kinase/Akt signaling pathway.
Author(s)	Blancher C, Moore JW, Robertson N, Harris AL
Institution	Imperial Cancer Research Fund, Molecular Oncology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom.
Source	Cancer Res 2001 Oct 1; 61(19):7349-55.
MeSH	1-Phosphatidylinositol 3-Kinase 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 Phosphoric Monoester Hydrolases Protein-Serine-Threonine Kinases Proteins Proto-Oncogene Proteins Proto-Oncogene Proteins c-akt RNA, Messenger Research Support, Non-U.S. Gov't 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
Abstract	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.
Language	eng
Pub Type(s)	Journal Article
PubMed ID	11585776

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