Retinoids exert profound effects on the growth and differentiation of normal, premalignant, and malignant epithelial cells in vitro and in vivo

Retinoids, metabolites and synthetic derivatives of vitamin A (retinol), have been shown to inhibit carcinogenesis in various epithelial tissues in animal model systems and to have clinical efficacy as chemotherapeutic agents against certain types ofcancer, including squamous cell carcinomas (SCCs). We examined the metabolism of[3H]retinol in normal human cell strains and SCC lines from the oral cavity and skin, and we report here that the cultured normal human epithellal cell strains esterifled [3Hjreti nol to a much greater extent than the SCC lines. Furthermore, microso mal extracts of normal cell strains (e.g., OKF4) exhibited about 7-fold more palmityl-CoA-dependent, phenylmethylsulfonyl fluoride-resistant retinol esterificatlon activity than extracts from SCC lines (e.g., SCC25). The fact that the esterification of retinol was phenylmethylsulfonyl fluo ride resistant suggests that the enzyme acyl-CoA:retinol acyltransferase is involved. Culture of both the normal and SCC lines in the presence of 1 @LMall-trans-retinoic acid (RA) for 48 h enhanced the formation of [3H]retinyl esters from [3H]retinoi All of the cell lines examined can also metabolize [3H]retinol to [3H]RA, [3H]14-hydroxy-4,14-retroretinol, [3H]retinaldehyde, and [3H]3,4-didehydroretinol, but this metabolism oc curs to varying extents in different cell lines. Culture of the cells in the presence of BA for 48 h did not affect the subsequent metabolism of [3H]retinol to [3H]RA and [3H]14-hydroxy-4,14-retroretinol, but it did reduce the metabolism of [3H]retinol to [3H]3,4-didehydroretinoL When cultured for 6—10 h in the presence of nanomolar concentrations of exogenous [3H]retinol, both the normal and SCC lines had much higher intracellular [3H]retinol concentrations, in the micromolar range. No cor relation was seen between CRABP II or CRBP I mRNA levels and the levels of either intracellular [3H]retinol or [3H]retlnol metabolism in these lines. The reduced ability to esterify retinolin these tumor cells may result in inappropriate cell growth and the loss of normal differentiation re sponses because ofthe lack ofa sufficient amount ofinternal retinol stored