ANDROGENS STIMULATE FATTY-ACID SYNTHASE IN THE HUMAN PROSTATE-CANCER CELL-LINE LNCAP

In addition to modulation of cell proliferation and stimulation of pro state-specific antigen secretion, one of the most striking effects of androgens on the human prostate cancer cell line LNCaP is the accumula tion of neutral lipids. These lipids are synthesized de novo, suggesti ng that LNCaP cells express all enzymes required for endogenous lipoge nesis and that the expression and/or activity of some of these enzymes is affected by androgens, One of the key enzymes involved in lipogene sis is fatty acid synthase (FAS), a potential prognostic enzyme and th erapeutic target that is found to be frequently overexpressed in a var iety of cancers including prostate cancer. Here, using Northern blot a nalysis, the gene encoding FAS is shown to be abundantly expressed in LNCaP cells and in two other prostate cancer cell lines tested (PC-3 a nd DU-145). In LNCaP cells, androgen treatment (10(-8) M R1881) causes a 3-4-fold increase in FAS mRNA levels, Concomitantly with the increa se in FAS gene expression, androgens induce a 10-12-fold stimulation o f FAS activity, Effects are dose- and time-dependent and follow course s similar to those of the androgen induction of lipid accumulation. In support of the involvement of the androgen receptor, steroid specific ity of regulation of EAS activity is in agreement with the aberrant li gand specificity of the mutated androgen receptor in LNCaP cells. Stim ulation of FAS activity is inhibited by the antiandrogen Casodex (bica lutamide) and is absent in the androgen receptor-negative cell lines P C-3 and DU-145. Taken together, these data demonstrate that androgens, mediated by the androgen receptor, stimulate the expression and activ ity 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.