Author(s): Mobley JA, Leav I, Zielie P, Wotkowitz C, Evans J,
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Abstract An enzyme previously identified as alpha-methylacyl-CoA racemase (AMACR) is overexpressed in high-grade prostatic intraepithelial neoplasia and in a majority (60-100\%) of prostate cancers (CaPs) as compared with normal and benign hyperplastic lesions of the prostate, where it is minimally expressed. This enzyme is required for the beta-oxidation of branched-chain fatty acids, which include phytanic acid and its alpha-oxidation product, pristanic acid. Interestingly, there is an established correlation between CaP risk and the consumption of dairy and beef products, which also contain marked quantities of these two phytols. In this context, it has also been reported that sex steroids influence lipogenesis through the induction of fatty acid synthase in CaP-derived cell lines and CaP tissues. These findings indicate a potential role for AMACR and the possible influence of sex steroids in both the early development and subsequent progression of CaP. Despite the recent interest in AMACR as a histological marker for CaP, little is known about the regulation of this enzyme and its role in CaP development. To identify potential AMACR-regulating factors, we treated LNCaP cells (an androgen-responsive CaP-derived cell line) and NPrEC cells (a normal prostate basal epithelial cell line) with increasing concentrations of pristanic acid, phytanic acid, 5alpha-dihydrotestosterone, and 17beta-estradiol. Neither the biologically potent androgen 5alpha-dihydrotestosterone nor 17beta-estradiol had any apparent effect on AMACR expression at the protein or transcriptional levels in either cell line. Conversely, pristanic acid and, to a much lesser extent, phytanic acid markedly increased AMACR protein levels selectively in the LNCaP cell line, but not the NPrEC cell line. However, no change was measured at the transcriptional level in either cell line. AMACR is therefore significantly increased at the protein level in CaP cells, through what appears to be the stabilizing effect of the same fatty acids that are present at appreciable concentrations in beef and dairy products, which have been associated with CaP risk. Our findings therefore provide a link between the consumption of dietary fatty acids and the enhanced expression of AMACR, an enzyme that may play an important role in genesis and progression of CaP.
This article was published in Cancer Epidemiol Biomarkers Prev
and referenced in Research & Reviews: Journal of Botanical Sciences