Article: article from journal or magazin.
NSAIDs inhibit alpha V beta 3 integrin-mediated and Cdc42/Rac-dependent endothelial-cell spreading, migration and angiogenesis.
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.
Animals, Anti-Inflammatory Agents, Non-Steroidal/pharmacology, Cell Division/drug effects, Cell Movement/drug effects, Cells, Cultured, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Cyclooxygenase Inhibitors/pharmacology, Dinoprostone/pharmacology, Endothelium, Vascular/cytology, Endothelium, Vascular/drug effects, Fibroblast Growth Factor 2/pharmacology, Humans, Isoenzymes/antagonists & inhibitors, Membrane Proteins, Mice, Mice, Nude, Neovascularization, Physiologic/drug effects, Nitrobenzenes/pharmacology, Prostaglandin-Endoperoxide Synthases, Receptors, Vitronectin/antagonists & inhibitors, Receptors, Vitronectin/metabolism, Sulfonamides/pharmacology, Thromboxane A2/pharmacology, cdc42 GTP-Binding Protein/drug effects, cdc42 GTP-Binding Protein/metabolism, rac GTP-Binding Proteins/drug effects, rac GTP-Binding Proteins/metabolism
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