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Overexpression of Retinoic Acid Receptor ß in Head and Neck Squamous Cell Carcinoma Cells Increases Their Sensitivity to Retinoid-induced Suppression of Squamous Differentiation by Retinoids¹

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 7703

Nuclear retinoic acid receptor ß (RARß) expression is suppressed in many head and neck squamous cell carcinomas (HNSCCs), and an inverse relationship was found between squamous differentiation and RARß expression in such cells. To investigate the role of RARß in HNSCC growth and differentiation, we transfected a retroviral RARß₂ expression vector (LNSß) into HNSCC SqCC/Y1 cells, which do not express endogenous RARß but do express RAR, RAR, and retinoid X receptors. Transfected clones expressing RARß₂ mRNA and protein exhibited enhanced sensitivity to the suppressive effects of all-trans-retinoic acid (ATRA) on squamous differentiation compared with cells transfected with the LNSX vector only; transglutaminase type I level was suppressed after a 3-day treatment with 10^-10 M ATRA in four of five LNSß clones, whereas it was not suppressed in LNSX cells even by 10^-6 M ATRA. Similarly, cytokeratin 1 mRNA level was more suppressed in ATRA-treated LNSß clones than it was in LNSX cells. This effect was independent of transrepression of activator protein-1. None of the LNSß-transfected clones showed an increased growth inhibition by ATRA, 9-cis-retinoic acid, or the synthetic retinoid 6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-naphthalenecarboxylic acid. These findings suggest that, in SqCC/Y1 cells, RARß mediates suppression of squamous differentiation by ATRA without enhancing its growth-inhibitory effects.

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