title: IGF-1 induced vascular endothelial growth factor secretion in head and neck squamous cell carcinoma.
abstract: Elevated vascular endothelial growth factor (VEGF) levels correlate with increased progression and poor prognosis of head and neck squamous cell carcinomas (HNSCC). VEGF expression is regulated by hypoxia and cytokines, including insulin-like growth factor-1 (IGF-1). In this report, we examined IGF-1 signaling and VEGF expression in SCC-9 cells. IGF-1 and the chemical hypoxia agent, cobalt chloride, each stimulated VEGF secretion and VEGF promoter activation. Cobalt chloride increased Hif-1alpha protein levels and HIF-1 dependent activation of the enolase promoter. IGF-1 increased these parameters only in the presence of cobalt chloride. IGF-1 stimulated PI-3K/Akt and Erk/MAPK pathways in SCC-9 cells, each contributing to Hif-1alpha expression and VEGF secretion. SCC-9 cells express the VEGF receptors Flk-1 and neuropilin-1, with VEGF treatment increasing VEGF promoter activity and VEGF secretion that was attenuated by the Flk-1 tyrosine kinase inhibitor, ZM 323881. These results demonstrate the presence of an IGF-1 regulated VEGF autocrine loop in HNSCC.
authors.affiliation: Department of Cell and Molecular Pharmacology and Experimental Therapeutics and Hollings Cancer Center, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Slomiany
authors.forename: Leigh Ann
authors.initials: LA
authors.lastname: Black
authors.forename: Megan M
authors.initials: MM
authors.lastname: Kibbey
authors.forename: Terry A
authors.initials: TA
authors.lastname: Day
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenzweig
mesh_terms: D019898:Autocrine Communication; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D002453:Cell Cycle; D003035:Cobalt / Q000494:pharmacology; D017077:Culture Media, Conditioned; D006258:Head and Neck Neoplasms / Q000378:metabolism*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D003035:Cobalt; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D040262:Receptors, Vascular Endothelial Growth Factor; D020928:Mitogen-Activated Protein Kinases; C018021:cobaltous chloride