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Cyclooxygenase-2 Inhibition Suppresses _vß₆ Integrin–Dependent Oral Squamous Carcinoma Invasion

¹ Tumour Biology Laboratory, Cancer Research UK Clinical Centre, Queen Mary's University, Charterhouse Square; ² Department of Histopathology, University College London, London, United Kingdom; ³ Biogen Idec, Cambridge, Massachusetts; and ⁴ Department of Oral Pathology, School of Dentistry, University of Sheffield, Sheffield, United Kingdom

Requests for reprints: Ian R. Hart or Gareth J. Thomas, Tumour Biology Laboratory, Cancer Research UK Clinical Centre, Queen Mary's University, Charterhouse Square, London EC1M 6BQ, United Kingdom. Phone: 44-20-70140409/0400; Fax: 44-20-70140401; E-mail: ian.hart{at}cancer.org.uk or gareth.thomas{at}cancer.org.uk.

Worldwide oral squamous cell carcinoma (OSCC) represents about 5.5% of all malignancies, with 30,000 new cases each year in the United States. The integrin _vß₆ and the enzyme cyclooxygenase-2 (COX-2) are implicated in OSCC progression and have been suggested as possible therapeutic targets. Each protein also is reported to identify dysplasias at high risk of malignant transformation, and current clinical trials are testing the efficacy of nonsteroidal anti-inflammatory drugs (NSAID) at preventing OSCC development. Given the probable increased expression of _vß₆ and COX-2 in OSCC and the inhibition of several integrins by NSAIDs, we investigated whether NSAIDs affected _vß₆-dependent cell functions. We found that expression of both _vß₆ and COX-2 was significantly higher in OSCC compared with oral epithelial dysplasias. Neither protein preferentially identified those dysplastic lesions that became malignant. Using OSCC cell lines, modified to express varying levels of _vß₆, we assessed the effect of COX-2 inhibition on cell invasion. We found that the COX-2 inhibitor NS398 inhibited specifically _vß₆-dependent, but not _vß₆-independent, OSCC invasion in vitro and in vivo, and this effect was modulated through prostaglandin E₂ (PGE₂)–dependent activation of Rac-1. Transient expression of constitutively active Rac-1, or addition of the COX-2 metabolite PGE₂, prevented the anti-invasive effect of NS398. Conversely, RNA interference down-regulation of Rac-1 inhibited _vß₆-dependent invasion. These findings suggest that COX-2 and _vß₆ interact in promoting OSCC invasion. This is a novel mechanism that, given the ubiquity of _vß₆ expression by head and neck cancers, raises the possibility that NSAIDs could protect against OSCC invasion. (Cancer Res 2006; 66(22): 10833-42)

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