Objectives: alphavbeta6 integrin is an epithelial-specific cell adhesion molecule, which is not expressed constitutively in healthy oral epithelia but is up-regulated early in the development of oral squamous cell carcinoma (OSCC) where expression correlates with malignant transformation. High alphavbeta6 expression occurs in over 90% of established OSCC. Cyclo-oxygenases (COXs) catalyse prostanoid biosynthesis, and are targets of non-steroidal anti-inflammatory drugs (NSAIDs). Similar to alphavbeta6, inducible COX-2 is expressed in oral dysplasias and OSCC. NSAIDs inhibit COXs and interestingly also inhibit several integrins. Our aim was to determine the effect of NSAIDs on alphavbeta6 function. Methods:Using cDNA-transfer techniques we previously created a panel of OSCC cell lines expressing varying levels of alphavbeta6, and showed that alphavbeta6 promotes tumour cell invasion. Using these cell lines we studied the effect of down-regulation of COX-2 activity on alphavbeta6-dependent invasion in Transwell assays and in organotypic cultures both in vitro and in vivo. Results:We found that COX-2 inhibition (20microM NS398) specifically blocked alphavbeta6-dependent invasion in Transwells (reduction=71%), organotypic cultures (reduction = >90%) and tumours in vivo (reduction=72%). COX-2 inhibition however, did not inhibit invasion of cells lacking alphavbeta6 (p=0.424, p=0.572, p=0.933 respectively). Levels of COX-2 protein were similar in all the cell lines and were not affected by alphavbeta6 inhibition. The mechanism by which NS398 suppressed alphavbeta6-dependent invasion was through inhibition of the GTPase, Rac-1. Down-regulating Rac-1 expression using RNAi inhibited alphavbeta6-dependent invasion to a similar degree as COX-2 inhibition. Conversely, expressing constitutively active Rac-1 (V12Rac-1-GFP) or adding the COX-2 metabolite, PGE2 (2ng/ml), abrogated the anti-invasive effect of NS398, suggesting that PGE2 is required for Rac-1 activation. Conclusion:A novel link between the COX-2 enzyme, alphavbeta6 and Rac-1 exists in OSCC invasion, raising the possibility that long-term treatment with NSAIDs has a rational basis for the prevention of the development and progression of OSCC.

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