Recent studies from our laboratory have indicated that the metabolism of
vitamin A (
retinol) to
retinyl esters, carried out primarily by the
enzyme lecithin:retinol acyltransferase (LRAT), is greatly reduced in human
carcinoma cell lines of the oral cavity, skin, breast, and kidney as compared with their normal epithelial counterparts. These studies suggest that human
carcinoma cells are
retinoid-deficient relative to normal epithelial cells. In this study, we examined the metabolism of [(3)H]
retinol and [(3)H]
retinoic acid (RA) in human
prostate cancer lines and in primary cultures of human prostate epithelial cells. Normal cells esterified all of the [(3)H]
retinol added to the cultures. In contrast, all seven
prostate cancer cell lines and four primary cultures derived from prostatic
adenocarcinomas metabolized only trace amounts of [(3)H]
retinol to [(3)H]
retinyl esters. Correlated with this relative lack of esterification of [(3)H]
retinol by the
cancer cells was loss of expression of
LRAT protein, whereas normal cells expressed abundant levels of
LRAT protein by Western analysis. The metabolism of [(3)H]RA was also examined in these prostatic cells. Two of the
prostate cancer tumor lines, DU 145 and PJ-1, exhibited rapid metabolism of [(3)H]RA; in contrast, the other
tumor lines or primary cultures metabolized [(3)H]RA at a much slower rate. We also found that the immortalization of normal human prostatic epithelial cells by SV40
T antigen led to a reduction in
LRAT protein expression and esterification of [(3)H]
retinol. Further transformation to tumorigenicity with the ras oncogene resulted in loss of detectable LRAT expression. Finally, we analyzed
LRAT protein expression in tissue sections from six
prostatectomy specimens by immunohistochemistry.
LRAT protein was predominantly expressed in the basal cells of normal prostatic epithelium, whereas its expression was lost in
prostate cancer. Collectively, these data implicate aberrant
retinoid metabolism in the process of prostatic
carcinogenesis.