Modulation of retinoic acid receptor function alters the growth inhibitoryresponse of oral SCC cells to retinoids

Retinoids have been shown to inhibit the growth of many human tumor cells i ncluding breast, ovarian and squamous cell carcinoma (SCC), While the exact mechanism of retinoid mediated growth suppression is not known, a role for the retinoic acid receptors (RARs) and retinoid X receptors (RXRs) has bee n established in both the breast and ovarian tumor cell models. We set out to determine if modulation of RAR/RXR function would alter the retinoid sen sitivity of oral SCC cells. We found that the growth of SCC cells was signi ficantly inhibited by treatment with either all-trans-retinoic acid (trans- RA) or the synthetic, conformationally restricted RAR gamma selective retin oids MM11254 and MM11389. In order to demonstrate a role for RAR/RXR functi on in this process, stable oral SCC cell clones constitutively overexpressi ng the dominant negative mutant RAR beta 2 (R269Q) were prepared and shown to exhibit reduced RAR/RXR transcriptional transactivation activity. We fou nd that oral SCC cells exhibiting reduced RAR/RXR function became resistant to growth inhibition by all-trans-RA, MM11254 and MM11389. Likewise, treat ment of oral SCC cells with the RAR gamma antagonist MM11253 was found to b lock the ability of MM11254 and MM11389 to inhibit SCC cell growth. Thus, m odulation of RAR function through the use of RAR-gamma selective agonists, an RAR-gamma selective antagonist or a pan-RAR dominant negative mutant sig nificantly alters the growth inhibitory response of oral SCC cells to retin oids.