The ability of retinoids to inhibit the growth of SCC cell lines has been known for some time. Recently, retinoids have been successfully used in vivo to prevent the progression of pre-neoplastic oral, bronchial, and head and neck lesions to frank malignant tumors. Retinoids have also been successfully employed in the treatment of squamous cell carcinomas. While retinoids have been used successfully in the treatment and prevention of oral SCC, for reasons yet to be understood, not all oral cancers are responsive to retinoid treatment. Moreover, the exact molecular mechanism by which retinoids alter growth in oral SCC cells remains to be determined. It is the goal of this application to directly address this question. The biological effects of retinoic acid are known to be mediated for the most part via unique members of the steroid hormone receptor superfamily, the nuclear retinoic acid receptors (RARs) and the nuclear retinoid X receptors (RXRs). The experiments proposed in this application will attempt to elucidate the precise role of the nuclear retinoic acid receptors in mediating the growth response of human oral SCC cells to retinoic acid (RA). More specifically, the plan is to investigate a number of potential mechanisms by which RARs and RXRs might act to inhibit growth in oral SCC cells. In particular, these studies will address the consequences of modulating RAR/RXR function on the function of growth regulatory transcription factors such as AP-1, cell cycle genes such as Rb, cyclins, cdks and cdk inhibitors. To achieve this goal the application proposes to: 1) determine if retinoid-dependent growth suppression of oral SCC cells can be modulated by changing the RA.R profile in these cells via altering the expression, overall composition and/or function individual RARs, RXRs or interacting co-factors; 2) determine the role of AP-1 antagonism in mediating the retinoid-dependent suppression of oral SCC cell growth; and 3) determine if retinoid-mediated growth suppression of oral SCC cells results from an alteration in expression and function of G-1 specific cell cycle regulatory genes including members of the Rb gene family (Rb, Rb-2/p 130. p107), cyclins (Dl, D2, D3), cdks (cdk2, cdk4, cdk6) and cdk inhibitors (p15, p16, p21, p27). Understanding the mechanism by which retinoids act to inhibit oral SCC growth will provide important and valuable information for the development of future oral cancer chemotherapeutic strategies.
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