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Unformatted text preview: [CANCER RESEARCH 60, 15411545, March 15, 2000] Advances in Brief Modulation of Hypoxia-inducible Factor 1 a Expression by the Epidermal Growth Factor/Phosphatidylinositol 3-Kinase/PTEN/AKT/FRAP Pathway in Human Prostate Cancer Cells: Implications for Tumor Angiogenesis and Therapeutics 1 Hua Zhong, Kelly Chiles, David Feldser, Erik Laughner, Colleen Hanrahan, Maria-Magdalena Georgescu, Jonathan W. Simons, 2 and Gregg L. Semenza The Johns Hopkins Oncology Center, Brady Urological Institute [H. Z., C. H., J. W. S.] and Departments of Pediatrics and Medicine and Institute of Genetic Medicine [K. C., D. F., E. L., G. L. S.], The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, and Laboratory of Molecular Oncology, The Rockefeller University, New York, New York 10021 [M-M. G.] Abstract Dysregulated signal transduction from receptor tyrosine kinases to phosphatidylinositol 3-kinase (PI3K), AKT (protein kinase B), and its effector FKBP-rapamycin-associated protein (FRAP) occurs via autocrine stimulation or inactivation of the tumor suppressor PTEN in many can- cers. Here we demonstrate that in human prostate cancer cells, basal-, growth factor-, and mitogen-induced expression of hypoxia-inducible fac- tor 1 (HIF-1) a , the regulated subunit of the transcription factor HIF-1, is blocked by LY294002 and rapamycin, inhibitors of PI3K and FRAP, respectively. HIF-1-dependent gene transcription is blocked by dominant- negative AKT or PI3K and by wild-type PTEN, whereas transcription is stimulated by constitutively active AKT or dominant-negative PTEN. LY294002 and rapamycin also inhibit growth factor- and mitogen- induced secretion of vascular endothelial growth factor, the product of a known HIF-1 target gene, thus linking the PI3K/PTEN/AKT/FRAP path- way, HIF-1, and tumor angiogenesis. These data indicate that pharmaco- logical agents that target PI3K, AKT, or FRAP in tumor cells inhibit HIF-1 a expression and that such inhibition may contribute to therapeutic efficacy. Introduction Tumor progression involves the selection of cells with somatic mutations that activate oncogenes and inactivate tumor suppressor genes. These mutations have the effect of driving cells through the cell cycle in an uncontrolled manner and preventing apoptosis. Two ad- aptations that are universal characteristics of solid tumors, indicating that they are necessary for tumor progression, are increased glycolytic metabolism and angiogenesis (reviewed in Ref. 1). These adaptations are also driven by genetic alterations in tumor cells, but their molec- ular basis has remained obscure. Loss of function mutations in tumor suppressor genes or activating mutations in oncogenes have been shown to dysregulate signal transduction pathways leading from growth factors (such as EGF 3 ) and their cognate receptor tyrosine kinases to PI3K, which catalyzes the conversion of phosphatidylinosi- tol 4-phosphate, and phosphatidylinositol 4,5-biphosphate to phos- phatidylinositol...
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