Cyclooxygenase-2 Inhibition Suppresses AvB6 Integrin–Dependent Oral Squamous Carcinoma Invasion

Worldwide oral squamous cell carcinoma (OSCC) represents about 5.5% of all malignancies, with f30,000 new cases each year in the United States. The integrin AvB6 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 AvB6 and COX-2 in OSCC and the inhibition of several integrins by NSAIDs, we investigated whether NSAIDs affected AvB6-dependent cell functions. We found that expression of both AvB6 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 AvB6, we assessed the effect of COX-2 inhibition on cell invasion. We found that the COX-2 inhibitor NS398 inhibited specifically AvB6-dependent, but not AvB6-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 AvB6-dependent invasion. These findings suggest that COX-2 and AvB6 interact in promoting OSCC invasion. This is a novel mechanism that, given the ubiquity of AvB6 expression by head and neck cancers, raises the possibility that NSAIDs could protect against OSCC invasion. (Cancer Res 2006; 66(22): 10833-42)