INDUCTION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR BY HYPOXIA IS MODULATED BY A PHOSPHATIDYLINOSITOL 3-KINASE AKT SIGNALING PATHWAY IN HA-RAS-TRANSFORMED CELLS THROUGH A HYPOXIA INDUCIBLE FACTOR-I TRANSCRIPTIONALELEMENT

Tumor angiogenesis, the development of new blood vessels, is a highly regulated process that is controlled genetically by alterations in onc ogene and tumor suppressor gene expression and physiologically by the tumor microenvironment, Previous studies indicate that the angiogenic switch in Ras-transformed cells may be physiologically promoted by the tumor microenvironment through the induction of the angiogenic mitoge n, vascular endothelial growth factor (VEGF). In this report, we show Pas-transformed cells do not use the downstream effecters c-Raf-1 or m itogen activated protein kinases (MAPK) in signaling VEGF induction by hypoxia as overexpression of kinase-defective alleles of these genes does not inhibit VEGF induction under low oxygen conditions. In contra st to the c-Raf-1/MAP kinase pathway, hypoxia increases phosphatidylin ositol 3-kinase (PI 3-kinase) activity in a Pas-dependent manner, and inhibition of PI 3-kinase activity genetically and pharmacologically r esults in inhibition of VEGF induction. We propose that hypoxia modula tes VEGF induction in Pas-transformed cells through the activation of a stress inducible PI 3-kinase/Akt pathway and the hypoxia inducible f actor-1 (HIF-1) transcriptional response element. (C) 1997 by The Amer ican Society of Hematology.