Phenotypic switching of VEGF and collagen XVIII during hypoxia in head and neck squamous carcinoma cells.
The present study sought to determine the potential role of stress activated MAPK and phosphatidylinositol 3-kinase (PI3K) signaling pathways in mediating phenotypic switching between angiogenic and angiostatic elements among squamous cell carcinoma (SCC) cell lines. In particular, we investigated the effects of hypoxia and those of cobalt chloride (CoCl(2)), which mimics the hypoxic response including the production of reactive oxygen species, on such phenotypic shifts. The expression and production of collagen XVIII, and CBP2/Hsp47 provided a measure of an angiostatic phenotype, while vascular endothelial growth factor (VEGF) expression was used to assess potential angiogenic states. These studies revealed that hypoxia produced a slight up-regulation of collagen XVIII and CBP2/Hsp47 that was inhibited by the stress kinase inhibitor SB203580 but was unaffected by N-acetylcysteine (NAC). In addition, VEGF expression was increased following hypoxia and this effect was reversed with inhibition of by SB203580. Conversely, CoCl(2) significantly diminished the expression of both collagen XVIII and CBP2/Hsp47 and enhanced VEGF expression. These changes were reversed by the PI3K inhibitor wortmannin and by treating cells with NAC. These studies show that phenotypic switching between collagen XVIII and VEGF is controlled by stress activated kinases under hypoxia, and PI3K signaling pathways as well as reactive oxygen species (ROS) following CoCl(2) treatment. Furthermore, modulation of the angiogenic switch is most profound during Akt activation than during activation of stress activated kinases.
D000111:Acetylcysteine / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D016587:Antimutagenic Agents / Q000494:pharmacology; D015415:Biomarkers / Q000032:analysis; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D003035:Cobalt / Q000494:pharmacology; D043170:Collagen Type XVIII / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D050958:HSP47 Heat-Shock Proteins; D006258:Head and Neck Neoplasms / Q000098:blood supply / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D009389:Neovascularization, Pathologic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D000077191:Wortmannin
D000111:Acetylcysteine; D000730:Androstadienes; D016587:Antimutagenic Agents; D015415:Biomarkers; D003035:Cobalt; D043170:Collagen Type XVIII; D004791:Enzyme Inhibitors; D050958:HSP47 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D007093:Imidazoles; D019869:Phosphatidylinositol 3-Kinases; D010726:Phosphodiesterase Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D042461:Vascular Endothelial Growth Factor A; D000077191:Wortmannin; C494660:SERPINH1 protein, human; C494918:AKT1 protein, human; C018021:cobaltous chloride; C093642:SB 203580