Swinnen J V, Esquenet M, Goossens K, Heyns W, Verhoeven G
Laboratory for Experimental Medicine and Endocrinology, Faculty of Medicine, Catholic University of Leuven, Belgium.
Cancer Res. 1997 Mar 15;57(6):1086-90.
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.
除了调节细胞增殖和刺激前列腺特异性抗原分泌外，雄激素对人前列腺癌细胞系LNCaP最显著的作用之一是中性脂质的积累。这些脂质是重新合成的，这表明LNCaP细胞表达内源性脂肪生成所需的所有酶，并且其中一些酶的表达和/或活性受雄激素影响。脂肪生成所涉及的关键酶之一是脂肪酸合酶（FAS），它是一种潜在的预后酶和治疗靶点，在包括前列腺癌在内的多种癌症中经常过度表达。在此，通过Northern印迹分析表明，编码FAS的基因在LNCaP细胞以及另外两种测试的前列腺癌细胞系（PC-3和DU-145）中大量表达。在LNCaP细胞中，雄激素处理（10(-8) M R1881）使FAS mRNA水平增加3至4倍。与FAS基因表达增加同时，雄激素诱导FAS活性增加10至12倍。这些效应具有剂量和时间依赖性，并且其过程与雄激素诱导脂质积累的过程相似。为支持雄激素受体的参与，FAS活性调节的类固醇特异性与LNCaP细胞中突变雄激素受体的异常配体特异性一致。FAS活性的刺激被抗雄激素药物比卡鲁胺（Casodex）抑制，并且在雄激素受体阴性的细胞系PC-3和DU-145中不存在。综上所述，这些数据表明，由雄激素受体介导的雄激素刺激FAS的表达和活性，并表明FAS活性的刺激至少代表了雄激素诱导LNCaP细胞中中性脂质积累的部分机制。
