Okadaic acid stimulates the expression of vascular endothelial growth factor gene.
Vascular endothelial growth factor (VEGF) is a specific mitogen for vascular endothelial cells and has been implicated in tumor angiogenesis. Okadaic acid, an inhibitor of protein phosphatases 1 and 2A, is a non-12-O-tetradecanoylphorbol-13-acetate (TPA)-type tumor promoter in two-stage carcinogenesis experiments in mouse skin. To elucidate the role of VEGF in the angiogenesis of these experimental tumors, the effect of okadaic acid on VEGF gene expression was examined. In NIH 3T3, Rat1, HeLa, and A431 cells, VEGF mRNA was upregulated by 5- to 10-fold after incubation with okadaic acid. Furthermore, the amount of VEGF protein in the culture medium was significantly increased after stimulation with okadaic acid. Interestingly, okadaic acid-induced upregulation of VEGF mRNA was not suppressed by protein kinase C (PKC) inhibitor or by tumor necrosis factor alpha blocking antibody, although TPA-induced VEGF upregulation was strongly suppressed by PKC inhibitor. Our results indicate that okadaic acid is a new and potent inducer of VEGF, suggesting the involvement of VEGF as an angiogenic factor during multistep carcinogenesis in vivo.
Wakiya
K
K
Department of Genetics, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-0071, Japan.
Shibuya
M
M
D016475:3T3 Cells; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D002460:Cell Line; D003470:Culture Media; D016228:Endothelial Growth Factors / Q000235:genetics* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D008222:Lymphokines / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000098:blood supply / Q000209:etiology; D009389:Neovascularization, Pathologic / Q000209:etiology; D009500:Neutralization Tests; D019319:Okadaic Acid / Q000494:pharmacology*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D011493:Protein Kinase C / Q000378:metabolism; D011714:Pyrans; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013141:Spiro Compounds; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000935:Antifungal Agents; D003470:Culture Media; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D008222:Lymphokines; D011714:Pyrans; D012333:RNA, Messenger; D013141:Spiro Compounds; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C053079:tautomycin; D019319:Okadaic Acid; D011493:Protein Kinase C; D010749:Phosphoprotein Phosphatases