Prosaposin is an AR-target gene and its neurotrophic domain upregulates AR expression and activity in prostate stromal cells
Prosaposin is an AR-target gene and its neurotrophic domain upregulates AR expression and activity in prostate stromal cells
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DOI：
10.1002/jcb.21786
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发表时间：
2008-08-15
影响因子：
4
通讯作者：
Garay, J.
中科院分区：
文献类型：
--
作者：
Koochekpour, S.;Lee, T. -J.;Garay, J.
最近的研究已经引入了鞘脂激活蛋白原（PSAP）作为前列腺癌（PCa）的多效生长因子。我们以前曾报道，PSAP或其已知的活性分子衍生物之一，saposin C作为雄激素激动剂和雄激素调节基因（ARG）的雄激素敏感（AS）PCa细胞系的功能。由于雄激素受体（AR）表达基质在前列腺癌中的潜在意义，我们评估了AR阳性前列腺基质（PrSt）细胞中DHT和PSAP之间可能的双向旁分泌调节相互作用。我们报告说，saposin C在一个配体非依赖性的方式增加AIR的表达，其核含量，和酪氨酸磷酸化。DHT处理PrSt细胞增加PSAP表达。我们还证明了位于PSAP启动子近端区域的先前表征的激素反应元件（HRE）的血清和雄激素诱导。此外，来自PrSt细胞和骨成纤维细胞的条件培养基（即，MSF）在雄激素非依赖性（AI）PC-3和AS LNCaP细胞中差异性地增加PSAP启动子活性。我们的数据首次表明，不仅saposin C或PSAP调节AR的表达/活性，但也作为一个ARG在PrSt。PSAP或saposin C在PCa和基质细胞中对AIR的配体非依赖性激活不仅可能在早期阶段促进前列腺癌发生，而且可能在雄激素缺乏的肿瘤微环境中促进疾病的AI进展。
Recent studies have introduced prosaposin (PSAP) as a pleiotrophic growth factor for prostate cancer (PCa). We have previously reported that PSAP or one of its known active molecular derivatives, saposin C functions as an androgen-agonist and androgen-regulated gene (ARG) for androgen-sensitive (AS) PCa cell lines. Due to the potential significance of androgen receptor (AR)-expressing stroma in PCa, we evaluated a possible bi-directional paracrine regulatory interactions between DHT and PSAP in AR-positive prostate stromal (PrSt) cells. We report that saposin C in a ligand-independent manner increased AIR expression, its nuclear content, and tyrosine phosphorylation. DHT treatment of PrSt cells increased PSAP expression. We also demonstrated both serum- and androgen-inducibility of a previously characterized hormone-responsive element (HRE) located in the proximal region of PSAP promoter. In addition, conditioned-media derived from PrSt cells and bone fibroblasts (i.e., MSF) differentially increased PSAP-promoter activity in androgen-independent (AI) PC-3 and AS LNCaP cells. Our data for the first time demonstrate that not only saposin C or PSAP regulates AR expression/activity, but also function as an ARG in PrSt. Ligand-independent activation of AIR by PSAP or saposin C in PCa and stromal cells may contribute not only to prostate carcinogenesis at an early stage, but also in AI progression of the disease in an androgen-deprived tumor microenvironment.