Dormond O, Foletti A, Paroz C, Rüegg C
Centre Pluridisciplinaire d'Oncologie, University of Lausanne Medical School, Lausanne, Switzerland.
Nat Med. 2001 Sep;7(9):1041-7. doi: 10.1038/nm0901-1041.
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.
环氧化酶-2（COX-2）是花生四烯酸代谢中的关键酶，在许多癌症中均有过表达。非甾体抗炎药（NSAIDs）对COX-2的抑制作用可降低人类患癌风险，并在动物模型中抑制肿瘤生长。NSAIDs的抗癌作用似乎涉及抑制肿瘤血管生成，但其潜在机制尚未完全明确。整合素αVβ3是一种黏附受体，在介导肿瘤血管生成中起关键作用。在此我们表明，NSAIDs对内皮细胞COX-2的抑制作用可抑制小GTP酶Cdc42和Rac的αVβ3依赖性激活，从而在体外抑制内皮细胞的铺展和迁移，并在体内抑制成纤维细胞生长因子-2诱导的血管生成。这些结果在COX-2、整合素αVβ3和Cdc42/Rac依赖性内皮细胞迁移之间建立了一种新的功能联系。此外，它们为理解NSAIDs的抗血管生成活性提供了理论依据。
