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Laboratory for Experimental Medicine and Endocrinology [J. V. S., M. E., W. H., G. V.] and Department of Biochemistry [K. G.], Faculty of Medicine, Onderwijs en Navorsing, Gasthuisberg, Catholic University of Leuven, B-3000 Leuven, Belgium
In addition to modulation of cell proliferation and stimulation of prostate-specific antigen secretion, one of the most striking effects of androgens on the human prostate cancer cell line LNCaP is the accumulation of neutral lipids. These lipids are synthesized de novo, suggesting that LNCaP cells express all enzymes required for endogenous lipogenesis and that the expression and/or activity of some of these enzymes is affected by androgens. One of the key enzymes involved in lipogenesis is fatty acid synthase (FAS), a potential prognostic enzyme and therapeutic target that is found to be frequently overexpressed in a variety of cancers including prostate cancer. Here, using Northern blot analysis, the gene encoding FAS is shown to be abundantly expressed in LNCaP cells and in two other prostate cancer cell lines tested (PC-3 and DU-145). In LNCaP cells, androgen treatment (10-8 M R1881) causes a 3–4-fold increase in FAS mRNA levels. Concomitantly with the increase in FAS gene expression, androgens induce a 10–12-fold stimulation of FAS activity. Effects are dose- and time-dependent and follow courses similar to those of the androgen induction of lipid accumulation. In support of the involvement of the androgen receptor, steroid specificity of regulation of FAS activity is in agreement with the aberrant ligand specificity of the mutated androgen receptor in LNCaP cells. Stimulation of FAS activity is inhibited by the antiandrogen Casodex (bicalutamide) and is absent in the androgen receptor-negative cell lines PC-3 and DU-145. Taken together, these data demonstrate that androgens, mediated by the androgen receptor, stimulate the expression and activity of FAS and suggest that stimulation of FAS activity represents at least part of the mechanism by which androgens induce the accumulation of neutral lipids in LNCaP cells.
1 Supported by Grant "Geconcerteerde Onderzoeksactie van de Vlaamse Gemeenschap," by Grant 3.0048.94 from the Belgian National Fund for Scientific Research (NFWO), and by a grant from the Vereniging voor Kankerbestrijding. Dr. J. Swinnen and K. Goossens are a senior research assistant and a research assistant, respectively, of the Belgian National Fund for Scientific Research (NFWO). M. Esquenet is the recipient of a grant from the Vlaamse kankerliga.
2 To whom requests for reprints should be addressed, at LEGENDO. Onderwijs en Navorsing. Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. Phone: (32) 16 34 59 70; Fax: (32) 16 34 59 34.
Received 9/ 9/96. Accepted 1/18/97.
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