Abstract
Cyclooxygenase-2 (COX-2), a key enzyme in arachidonic acid metabolism, is overexpressed in many cancers. Inhibition of COX-2 by nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of cancer development in humans and suppresses tumor growth in animal models. The anti-cancer effect of NSAIDs seems to involve suppression of tumor angiogenesis, but the underlying mechanism is not completely understood. Integrin alpha V beta 3 is an adhesion receptor critically involved in mediating tumor angiogenesis. Here we show that inhibition of endothelial-cell COX-2 by NSAIDs suppresses alpha V beta 3-dependent activation of the small GTPases Cdc42 and Rac, resulting in inhibition of endothelial-cell spreading and migration in vitro and suppression of fibroblast growth factor-2-induced angiogenesis in vivo. These results establish a novel functional link between COX-2, integrin alpha V beta 3 and Cdc42-/Rac-dependent endothelial-cell migration. Moreover, they provide a rationale to the understanding of the anti-angiogenic activity of NSAIDs.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Cell Division / drug effects
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Cell Movement / drug effects
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Cells, Cultured
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Cyclooxygenase 2
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors / pharmacology
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Dinoprostone / pharmacology
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Endothelium, Vascular / cytology*
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / physiology
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Fibroblast Growth Factor 2 / pharmacology
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Humans
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Isoenzymes / antagonists & inhibitors
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Membrane Proteins
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Mice
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Mice, Nude
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Neovascularization, Physiologic / drug effects
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Nitrobenzenes / pharmacology
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Prostaglandin-Endoperoxide Synthases
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Receptors, Vitronectin / antagonists & inhibitors
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Receptors, Vitronectin / metabolism*
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Sulfonamides / pharmacology
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Thromboxane A2 / pharmacology
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cdc42 GTP-Binding Protein / drug effects
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cdc42 GTP-Binding Protein / metabolism*
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rac GTP-Binding Proteins / drug effects
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rac GTP-Binding Proteins / metabolism*
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors
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Isoenzymes
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Membrane Proteins
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Nitrobenzenes
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Receptors, Vitronectin
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Sulfonamides
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Fibroblast Growth Factor 2
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N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
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Thromboxane A2
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Cyclooxygenase 2
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases
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cdc42 GTP-Binding Protein
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rac GTP-Binding Proteins
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Dinoprostone