METABOLISM OF ALL-TRANS-RETINOL IN NORMAL HUMAN CELL STRAINS AND SQUAMOUS-CELL CARCINOMA (SCC) LINES FROM THE ORAL CAVITY AND SKIN - REDUCED ESTERIFICATION OF RETINOL IN SCC LINES

Retinoids, metabolites and synthetic derivatives of vitamin A (retinol ), have been shown to inhibit carcinogenesis in various epithelial tis sues In animal model systems and to have clinical efficacy as chemothe rapeutic agents against certain types of cancer, including squamous ce ll carcinomas (SCCs). We examined the metabolism of [H-3]retinol in no rmal human cell strains and SCC lines from the oral cavity and skin, a nd we report here that the cultured normal human epithelial cell strai ns esterified [H-3]retinol to a much greater extent than the SCC lines . Furthermore, microsomal extracts of normal cell strains (e.g., OKF4) exhibited about 7-fold more palmityl-CoA-dependent, phenylmethylsulfo nyl fluoride-resistant retinol esterification activity than extracts f rom SCC lines (e.g., SCC25). The fact that the esterification of retin ol was phenylmethylsulfonyl fluoride resistant suggests that the enzym e acyl-CoA:retinol acyltransferase is involved. Culture of both the no rmal and SCC lines in the presence of 1 mu M all-trans-retinoic acid ( RA) for 48 h enhanced the formation of [H-3]retinyl esters from [H-3]r etinol, All of the cell lines examined can also metabolize [H-3]retino l to [H-3]RA, [H-3]14-hydroxy-4,14-retroretinol, [H-3]retinaldehyde, a nd [H-3]3,4-didehydroretinol, but this metabolism occurs to varying ex tents in different cell lines. Culture of the cells in the presence of RA for 48 h did not affect the subsequent metabolism of [H-3]retinol to [H-3]RA and [H-3]14-hydroxy-4,14-retroretinol, but it did reduce th e metabolism of [H-3]retinol to [3H]3,4-didehydroretinol. When culture d for 6-10 h in the presence of nanomolar concentrations of exogenous [H-3]retinol, both the normal and SCC lines had much higher intracellu lar [H-3]retinol concentrations, in the micromolar range. No correlati on was seen between CRABP II or CRBP I mRNA levels and the levels of e ither intracellular [H-3]retinol or [H-3]retinol metabolism in these l ines. The reduced ability to esterify retinol in these tumor cells may result in inappropriate cell growth and the loss of normal differenti ation responses because of the lack of a sufficient amount of internal retinol stored as retinyl esters.