Modulation of hypoxia-inducible factor 1 alpha expression by the epidermalgrowth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in humanprostate cancer cells: Implications for tumor angiogenesis and therapeutics

Dysregulated signal transduction from receptor tyrosine kinases to phosphat idylinositol 3-kinase (PI3K), AKT (protein kinase B), and its effector FKBP -rapamycin-associated protein (FRAP) occurs via autocrine stimulation or in activation of the tumor suppressor PTEN in many cancers. Here we demonstrat e that in human prostate cancer cells, basal-, growth factor-, and mitogen- induced expression of hypoxia-inducible factor 1 (HIF-1) alpha, the regulat ed subunit of the transcription factor HIF-1, is blocked by LY294002 and ra pamycin, inhibitors of PI3K and FRAP, respectively. HIF-1-dependent gene tr anscription is blocked by dominant-negative AKT or PI3K and by wild-type PT EN, whereas transcription is stimulated by constitutively active AKT or dom inant-negative PTEN. LY294002 and rapamycin also inhibit growth factor- and mitogen-induced secretion of vascular endothelial growth factor, the produ ct of a known HIF-1 target gene, thus linking the PI3K/PTFN/AKT/FRAP pathwa y, HIF-1, and tumor angiogenesis, These data indicate that pharmacological agents that target PI3K, AKT, or FRAP in tumor cells inhibit HIF-1 alpha ex pression and that such inhibition may contribute to therapeutic efficacy.