Effects of ras and von Hippel-Lindau (VHL) gene mutations on hypoxia-inducible factor (HIF)-1α, HIF-2α, and vascular endothelial growth factor expression and their …

C Blancher, JW Moore, N Robertson, AL Harris - Cancer research, 2001 - AACR
C Blancher, JW Moore, N Robertson, AL Harris
Cancer research, 2001AACR
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)-1α and HIF-
2α expression and on endogenous VEGF responses to hypoxia. A panel of breast cancer …
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)-1α and HIF-2α 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-1α induction and phosphorylation under hypoxia. However, HIF-2α 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-1α and HIF-2α expression. This effect was blocked by PI3K inhibitor, demonstrating one mechanism for ras synergy with hypoxia-mediated induction of genes. The decreased HIF-1α expression was not dependent on VHL interaction because a renal carcinoma cell line with VHL mutation and constitutive high HIF-1α expression also showed down-regulation of HIF-1α 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.
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