Cyclooxygenase-2 inhibition suppresses αvβ6 integrin-dependent oral squamous carcinoma invasion

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 α v β 6 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 α v β 6 and COX-2 in OSCC and the inhibition of several integrins by NSAIDs, we investigated whether NSAIDs affected α v β 6 -dependent cell functions. We found that expression of both α v β 6 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 α v β 6 , we assessed the effect of COX-2 inhibition on cell invasion. We found that the COX-2 inhibitor NS398 inhibited specifically α v β 6 -dependent, but not α v β 6 -independent, OSCC invasion in vitro and in vivo , and this effect was modulated through prostaglandin E 2 (PGE 2 )–dependent activation of Rac-1. Transient expression of constitutively active Rac-1, or addition of the COX-2 metabolite PGE 2 , prevented the anti-invasive effect of NS398. Conversely, RNA interference down-regulation of Rac-1 inhibited α v β 6 -dependent invasion. These findings suggest that COX-2 and α v β 6 interact in promoting OSCC invasion. This is a novel mechanism that, given the ubiquity of α v β 6 expression by head and neck cancers, raises the possibility that NSAIDs could protect against OSCC invasion. (Cancer Res 2006; 66(22): 10833-42)