Expression of retinoic acid receptor gamma correlates with retinoic acid sensitivity and metabolism in head and neck squamous cell carcinoma cell lines

Retinoids, analogues of vitamin A, can reverse premalignant lesions and pre vent second primary tumors in patients with head and neck squamous cell car cinoma (HNSCC). The effects of retinoids are mediated by retinoic acid rece ptors (RARs) and retinoid X receptors (RXRs), which act as ligand-activated transcription factors. The regulation of cell growth, differentiation and retinoid metabolism in normal, premalignant and malignant cells by retinoid s is thought to be a result of their effects on gene expression. We investi gated mRNA expression of RARs (alpha, beta, and gamma) and RXR-beta by mean s of RNase protection and related this to retinoic acid (RA)induced growth inhibition and RA turnover in four HNSCC cell lines (UM-SCC-14C, UM-SCC-22A , UM-SCC-35 and VU-SCC-OE). An RA-resistant subline of UM-SCC-35 was genera ted by exposure to increasing concentrations of RA for 8 months (designated UM-SCC-35R), RA turnover was determined on the basis of decreasing RA leve ls in the cells and culture medium after exposure to 1 muM RA, WE found tha t RAR-gamma mRNA expression was strongly correlated with RA-induced growth inhibition (p = 0.016, R 0.92) and RA turnover(p = 0.041, R = 0.86), RAR-be ta transcript levels were reduced in three of five cell lines compared with normal mucosa, and these did not correlate with RA-induced growth inhibiti on and RA turnover Expression of RAR-alpha and RXR-beta was not substantial ly altered in any of the cell lines, These findings suggest that in HNSCC c ell lines RAR-gamma is the most important retinoid receptor for regulation of RA turnover rate and RA-induced growth inhibition. (C) 2001 Wiley-Liss, Inc.