Guo Xiaojia, Knudsen Beatrice S, Peehl Donna M, Ruiz Alberto, Bok Dean, Rando Robert R, Rhim Johng S, Nanus David M, Gudas Lorraine J
Department of Pharmacology, Weill Medical College of Cornell University, New York, New York 10021, USA.
Cancer Res. 2002 Mar 15;62(6):1654-61.
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.
我们实验室最近的研究表明，与正常上皮细胞相比，口腔、皮肤、乳腺和肾脏的人类癌细胞系中，主要由卵磷脂：视黄醇酰基转移酶（LRAT）催化的维生素A（视黄醇）向视黄酯的代谢大大减少。这些研究表明，相对于正常上皮细胞，人类癌细胞缺乏类维生素A。在本研究中，我们检测了人类前列腺癌细胞系和原代培养的人类前列腺上皮细胞中[³H]视黄醇和[³H]视黄酸（RA）的代谢情况。正常细胞将添加到培养物中的所有[³H]视黄醇酯化。相比之下，所有七个前列腺癌细胞系和四个源自前列腺腺癌的原代培养物仅将微量的[³H]视黄醇代谢为[³H]视黄酯。与癌细胞对[³H]视黄醇酯化相对缺乏相关的是LRAT蛋白表达的丧失，而通过蛋白质免疫印迹分析，正常细胞表达大量的LRAT蛋白。我们还检测了这些前列腺细胞中[³H]RA的代谢情况。两个前列腺癌肿瘤系DU 145和PJ - 1表现出[³H]RA的快速代谢；相比之下，其他肿瘤系或原代培养物代谢[³H]RA的速度要慢得多。我们还发现，用SV40 T抗原使正常人类前列腺上皮细胞永生化会导致LRAT蛋白表达和[³H]视黄醇酯化减少。用ras癌基因进一步转化为致瘤性会导致可检测到的LRAT表达丧失。最后，我们通过免疫组织化学分析了六个前列腺切除标本组织切片中的LRAT蛋白表达。LRAT蛋白主要在正常前列腺上皮的基底细胞中表达，而在前列腺癌中其表达丧失。总体而言，这些数据表明类维生素A代谢异常与前列腺癌发生过程有关。
