Overexpression of retinoic acid receptor beta in head and neck squamous cell carcinoma cells increases their sensitivity to retinoid-induced suppression of squamous differentiation by retinoids.
Nuclear retinoic acid receptor beta(RARbeta) expression is suppressed in many head and neck squamous cell carcinomas (HNSCCs), and an inverse relationship was found between squamous differentiation and RARbeta expression in such cells. To investigate the role of RARbeta in HNSCC growth and differentiation, we transfected a retroviral RARbeta2 expression vector (LNSbeta) into HNSCC SqCC/Y1 cells, which do not express endogenous RARbeta but do express RARalpha, RARgamma, and retinoid X receptors. Transfected clones expressing RARbeta2 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 LNSbeta 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 LNSbeta clones than it was in LNSX cells. This effect was independent of transrepression of activator protein-1. None of the LNSbeta-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-naphthale necarboxylic acid. These findings suggest that, in SqCC/Y1 cells, RARbeta mediates suppression of squamous differentiation by ATRA without enhancing its growth-inhibitory effects.
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
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D016475:3T3 Cells / Q000187:drug effects; D000077556:Alitretinoin; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D004351:Drug Resistance / Q000235:genetics; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D009281:Naphthalenes / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis* / Q000235:genetics; D012176:Retinoids / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D009281:Naphthalenes; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D018808:Transcription Factor AP-1; C082925:retinoic acid receptor beta; D000077556:Alitretinoin; D014212:Tretinoin; C039575:6-(1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-naphthyl)-2-naphthalenecarboxylic acid