Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
Prostate. 2010 Feb 15;70(3):239-51. doi: 10.1002/pros.21057.
De novo androgen synthesis and subsequent androgen receptor (AR) activation has recently been shown to contribute to castration-resistant prostate cancer (CRPC) progression. Herein we provide evidence that fatty acids (FA) can trigger androgen synthesis within steroid starved prostate cancer (CaP) tumor cells.
Tumoral FA and steroid levels were assessed by GC-MS and LC-MS, respectively. Profiles of genes and proteins involved in FA activation of steroidogenesis were assessed by fluorescence microscopy, immunohistochemistry, microarray expression profiling and Western blot analysis.
In human CaP tissues the levels of proteins responsible for FA activation of steroid synthesis were observed to be altered during progression to CRPC. Further investigating this mechanism in LNCaP cells, we demonstrate that specific FA, arachidonic acid, is synthesized in an androgen-dependent and AR-mediated manner. Arachidonic acid is known to induce steroidogenic acute regulatory protein (StAR) in steroidogenic cells. When bound to hormone sensitive lipase (HSL), StAR shuttles free cholesterol into the mitochondria for downstream conversion into androgens. We show that arachidonic acid induces androgen production in steroid starved LNCaP cells coincidently in the same conditions that HSL and StAR are predominantly localized in the mitochondria. Furthermore, their activities are verified by a functional increase in mitochondrial uptake of cholesterol in this steroid starved environment.
We propose that this characterized arachidonic acid induced steroidogenesis mechanism significantly contributes to the activation of AR in CRPC progression and therefore recommend that fatty acid pathways be targeted therapeutically in progressing CaP.
新的雄激素合成和随后的雄激素受体 (AR) 激活最近被证明有助于去势抵抗性前列腺癌 (CRPC) 的进展。在此，我们提供了证据表明脂肪酸 (FA) 可以在类固醇饥饿的前列腺癌 (CaP) 肿瘤细胞内触发雄激素合成。
通过 GC-MS 和 LC-MS 分别评估肿瘤中的 FA 和类固醇水平。通过荧光显微镜、免疫组织化学、微阵列表达谱分析和 Western blot 分析评估参与 FA 激活类固醇生成的基因和蛋白质谱。
在人 CaP 组织中，观察到负责 FA 激活类固醇合成的蛋白质水平在向 CRPC 进展过程中发生改变。在 LNCaP 细胞中进一步研究这种机制，我们证明特定的 FA，花生四烯酸，以雄激素依赖和 AR 介导的方式合成。花生四烯酸已知在类固醇生成细胞中诱导类固醇生成急性调节蛋白 (StAR)。当与激素敏感脂肪酶 (HSL) 结合时，StAR 将游离胆固醇穿梭到线粒体中，用于下游转化为雄激素。我们表明，花生四烯酸在类固醇饥饿的 LNCaP 细胞中诱导雄激素产生，与 HSL 和 StAR 主要定位于线粒体的条件相同。此外，在这种类固醇饥饿的环境中，通过功能性增加线粒体摄取胆固醇来验证它们的活性。
我们提出，这种特征化的花生四烯酸诱导的类固醇生成机制极大地促进了 AR 在 CRPC 进展中的激活，因此建议在进展性 CaP 中针对脂肪酸途径进行治疗。
