Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics
| Autor: | H, Zhong, K, Chiles, D, Feldser, E, Laughner, C, Hanrahan, M M, Georgescu, J W, Simons, G L, Semenza |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
Male
Vascular Endothelial Growth Factor A Morpholines Enzyme-Linked Immunosorbent Assay Endothelial Growth Factors Protein Serine-Threonine Kinases Culture Media Serum-Free Phosphatidylinositol 3-Kinases Proto-Oncogene Proteins Tumor Cells Cultured Humans Enzyme Inhibitors Immunophilins Hypoxia Phosphoinositide-3 Kinase Inhibitors Lymphokines Epidermal Growth Factor Neovascularization Pathologic Vascular Endothelial Growth Factors TOR Serine-Threonine Kinases Tumor Suppressor Proteins PTEN Phosphohydrolase Nuclear Proteins Prostatic Neoplasms Hypoxia-Inducible Factor 1 alpha Subunit Phosphoric Monoester Hydrolases DNA-Binding Proteins Phosphotransferases (Alcohol Group Acceptor) Chromones Tetradecanoylphorbol Acetate Hypoxia-Inducible Factor 1 Carrier Proteins Proto-Oncogene Proteins c-akt Signal Transduction Transcription Factors |
| Zdroj: | Cancer research. 60(6) |
| ISSN: | 0008-5472 |
| Popis: | 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) alpha, 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-1alpha expression and that such inhibition may contribute to therapeutic efficacy. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|