PT  - JOURNAL ARTICLE
AU  - Zhong, Hua
AU  - Chiles, Kelly
AU  - Feldser, David
AU  - Laughner, Erik
AU  - Hanrahan, Colleen
AU  - Georgescu, Maria-Magdalena
AU  - Simons, Jonathan W.
AU  - Semenza, Gregg L.
TI  - Modulation of Hypoxia-inducible Factor 1α Expression by the Epidermal Growth Factor/Phosphatidylinositol 3-Kinase/PTEN/AKT/FRAP Pathway in Human Prostate Cancer Cells: Implications for Tumor Angiogenesis and Therapeutics
DP  - 2000 Mar 15
TA  - Cancer Research
PG  - 1541--1545
VI  - 60
IP  - 6
4099  - http://cancerres.aacrjournals.org/content/60/6/1541.short
4100  - http://cancerres.aacrjournals.org/content/60/6/1541.full
SO  - Cancer Res2000 Mar 15; 60
AB  - 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 cancers. Here we demonstrate that in human prostate cancer cells, basal-, growth factor-, and mitogen-induced expression of hypoxia-inducible factor 1 (HIF-1) α, 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 pathway, HIF-1, and tumor angiogenesis. These data indicate that pharmacological agents that target PI3K, AKT, or FRAP in tumor cells inhibit HIF-1α expression and that such inhibition may contribute to therapeutic efficacy.