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NSAIDs inhibit αVβ3 integrin-mediated and Cdc42/Rac-dependent endothelial-cell spreading, migration and angiogenesis

Nature Medicine volume 7, pages 1041–1047 (2001)Cite this article

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 αVβ3 is an adhesion receptor critically involved in mediating tumor angiogenesis. Here we show that inhibition of endothelial-cell COX-2 by NSAIDs suppresses αVβ3-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 αVβ3 and Cdc42-/Rac-dependent endothelial-cell migration. Moreover, they provide a rationale to the understanding of the anti-angiogenic activity of NSAIDs.

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Figure 1: NSAIDs inhibit αVβ3-mediated endothelial-cell spreading and migration.
Figure 2: Dose-response and COX-2 expression in HUVECs.
Figure 3: PGE2 and PGI2 reverse the suppression of HUVEC spreading and migration on vitronectin caused by NS-398.
Figure 4: Inhibition of COX-2 interferes with integrin-post receptor events.
Figure 5: NS-398 and indomethacin suppress αVβ3-dependent activation of Cdc42 and Rac.
Figure 6: Retroviral delivery of constitutive active Rac reverses the suppression of FGF2-induced angiogenesis caused by NS-398 in the murine Matrigel angiogenesis assay.

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Acknowledgements

The authors thank F.J. Lejeune for continuous support, P. Saudan, M. Ginsberg and S. Klein for providing reagents, R. Stupp and A. Wilson for discussion and critical reading of the manuscript, J. Bamat for help with immunohistological techniques and P. Dubied for photo artwork. This work was supported by grants from the Swiss National Science Foundation (31-52946.97), the Swiss Cancer League, the Leenaards Foundation and the BCV Foundation.

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  1. Centre Pluridisciplinaire d'Oncologie, University of Lausanne Medical School, Lausanne, Switzerland

    Olivier Dormond, Alessandro Foletti, Cécile Paroz & Curzio Rüegg

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Correspondence to Curzio Rüegg.

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Dormond, O., Foletti, A., Paroz, C. et al. NSAIDs inhibit αVβ3 integrin-mediated and Cdc42/Rac-dependent endothelial-cell spreading, migration and angiogenesis. Nat Med 7, 1041–1047 (2001). https://doi.org/10.1038/nm0901-1041

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