Impact of Cox‐2 on estrogen receptor beta action in prostate epithelial cells

项目总结： 前列腺炎症是症状性良性前列腺增生症(BPH)的共同特征，可能会改变 细胞因子诱导促炎性细胞因子在良性前列腺增生症中的作用 信号介质如环氧合酶-2(COX-2)。COX-2在大鼠子宫腔上皮细胞中过表达 BPH组织，但主要位于慢性炎症区域。一项临床试验只报告了一个短期的 COX-2抑制剂(即非类固醇抗炎药，如罗非昔布)在减少 与5AR抑制剂联合使用时出现LUTS症状。临床局限性的发生机制 抑制COX-2的有效性尚不清楚。在人BPH-1前列腺上皮细胞系(该细胞系 表达高基础水平的COX-2)，药物或分子消融COX-2表达限制了 内质网通过选择性干扰类固醇合成酶的表达而发挥保护作用 睾丸素减少了ER？配体的产生。因此，我们假设有限的有效性 在目前的BPH临床试验中，NSAIDs的主要原因是前列腺癌类固醇合成途径的中断 组织保护性受体的配体。提出了四个目标来检验这一假设：目标1将决定 环氧合酶-2对前内皮细胞产生内质网配体的影响AIM 2将确定全基因组的基础和ER？调节 COX-2过表达的急性或长期适应性反应对基因表达模式的影响 PrECs。目标3将确定环氧合酶-2和内质网对极化上皮细胞功能相关靶点的影响 在PrECs和ER？基因敲除小鼠的三维培养中。目标4将确定COX-2对内质网的影响 人前列腺组织中的信号转导与前列腺炎症的啮齿动物模型

Project Summary: Prostatic inflammation is a common feature of symptomatic benign prostatic hyperplasia (BPH) and may alter epithelial cell proliferation and tissue homeostasis in BPH through cytokine induction of proinflammatory signaling mediators such as cyclooxygenase-2 (Cox-2). Cox-2 is overexpressed in luminal epithelial cells of BPH tissue but predominantly in regions of chronic inflammation. One clinical trial reported only a short-term benefit of a Cox-2 inhibitor (i.e. nonsteroidal anti-inflammatory agents [NSAIDs] such as rofecoxib) in reducing LUTS symptoms when combined with a 5AR inhibitor. The mechanism responsible for the limited clinical effectiveness of Cox-2 inhibition is not known. In the human BPH-1 prostate epithelial cell line (which expresses high basal levels of Cox-2), pharmacologic or molecular ablation of Cox-2 expression limits the protective effects of ERß through selective disruptions in steroidogenic enzyme expression leading to a reduced production of ERß ligands from testosterone. We therefore hypothesize that the limited effectiveness of NSAIDs in current BPH clinical trials is due to disruptions in prostatic steroidogenic pathways that generate ligands for the tissue protective ERß. Four Aims are proposed to test this hypothesis: Aim 1 will determine the impact of Cox-2 on ERß ligand production in PrECs. Aim 2 will identify genome-wide basal and ERß-regulated gene expression patterns influenced by acute or long-term adaptive responses to Cox-2 overexpression in PrECs. Aim 3 will identify the impact of Cox-2 and ERß on targets relevant to polarized epithelial cell function in 3- dimensional cultures of PrECs and ERß knockout mice. Aim 4 will determine the impact of Cox-2 on ERß signaling in human prostate explants and a rodent model of prostatic inflammation