title: Evidence for a role of p38 kinase in hypoxia-inducible factor 1-independent induction of vascular endothelial growth factor expression by sodium arsenite.
abstract: Recently we have demonstrated that sodium arsenite induces the expression of hypoxia-inducible factor 1alpha (HIF-1alpha) protein and vascular endothelial growth factor (VEGF) in OVCAR-3 human ovarian cancer cells. We now show that arsenic trioxide, an experimental anticancer drug, exerts the same effects. The involvement of phosphatidylinositol 3-kinase and mitogen-activated protein kinase (MAPK) pathways in the effects of sodium arsenite was investigated. By using kinase inhibitors in OVCAR-3 cells, both effects of sodium arsenite were found to be independent of phosphatidylinositol 3-kinase and p44/p42 MAPKS but were attenuated by inhibition of p38 MAPK. A role for p38 in the regulation of HIF-1alpha and VEGF expression was supported further by analysis of activation kinetics. Experiments in mouse fibroblast cell lines, lacking expression of c-Jun N-terminal kinases 1 and 2, suggested that these kinases are not required for induction of HIF-1alpha protein and VEGF mRNA. Unexpectedly, sodium arsenite did not activate a HIF-1-dependent reporter gene in OVCAR-3 cells, indicating that functional HIF-1 was not induced. In agreement with this hypothesis, up-regulation of VEGF mRNA was not reduced in HIF-1alpha(-/-) mouse fibroblast cell lines. Altogether, these data suggest that not HIF-1, but rather p38, mediates induction of VEGF mRNA expression by sodium arsenite.
authors.affiliation: Department of Medical Oncology, Vrije Universiteit Medical Center, Amsterdam 1081 HV, The Netherlands. mca.duyndam.oncol@med.vu.nl
authors.forename: Monique C A
authors.initials: MC
authors.lastname: Duyndam
authors.forename: Saskia T M
authors.initials: ST
authors.lastname: Hulscher
authors.forename: Elsken
authors.initials: E
authors.lastname: van der Wall
authors.forename: Herbert M
authors.initials: HM
authors.lastname: Pinedo
authors.forename: Epie
authors.initials: E
authors.lastname: Boven
mesh_terms: D000818:Animals; D018053:Arsenites / Q000494:pharmacology*; D015153:Blotting, Western; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016228:Endothelial Growth Factors / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D048031:JNK Mitogen-Activated Protein Kinases; D007700:Kinetics; D008156:Luciferases / Q000378:metabolism; D008222:Lymphokines / Q000096:biosynthesis*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D012260:Ribonucleases / Q000378:metabolism; D017670:Sodium Compounds / Q000494:pharmacology*; D013347:Subcellular Fractions; D013997:Time Factors; D014157:Transcription Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D018053:Arsenites; D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D009687:Nuclear Proteins; D012333:RNA, Messenger; D017670:Sodium Compounds; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C017947:sodium arsenite; D008156:Luciferases; D019869:Phosphatidylinositol 3-Kinases; D048056:Mitogen-Activated Protein Kinase 9; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D012260:Ribonucleases