Sampson Natalie, Koziel Rafal, Zenzmaier Christoph, Bubendorf Lukas, Plas Eugen, Jansen-Dürr Pidder, Berger Peter
Institute of Biomedical Aging Research, Austrian Academy of Science, Rennweg 10, Innsbruck, Austria.
Mol Endocrinol. 2011 Mar;25(3):503-15. doi: 10.1210/me.2010-0340. Epub 2011 Jan 27.
Stromal remodeling, in particular fibroblast-to-myofibroblast differentiation, is a hallmark of benign prostatic hyperplasia (BPH) and solid tumors, including prostate cancer (PCa). Increased local production of TGFβ1 is considered the inducing stimulus. Given that stromal remodeling actively promotes BPH/PCa development, there is considerable interest in developing stromal-targeted therapies. Microarray and quantitative PCR analysis of primary human prostatic stromal cells induced to undergo fibroblast-to-myofibroblast differentiation with TGFβ1 revealed up-regulation of the reactive oxygen species (ROS) producer reduced nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) and down-regulation of the selenium-containing ROS-scavenging enzymes glutathione peroxidase 3, thioredoxin reductase 1 (TXNRD1), and the selenium transporter selenoprotein P plasma 1. Consistently, NOX4 expression correlated specifically with the myofibroblast phenotype in vivo, and loss of selenoprotein P plasma 1 was observed in tumor-associated stroma of human PCa biopsies. Using lentiviral NOX4 short hairpin RNA-mediated knockdown, pharmacological inhibitors, antioxidants, and selenium, we demonstrate that TGFβ1 induction of NOX4-derived ROS is required for TGFβ1-mediated phosphorylation of c-jun N-terminal kinase, which in turn is essential for subsequent downstream cytoskeletal remodeling. Significantly, selenium supplementation inhibited differentiation by increasing ROS-scavenging selenoenzyme biosynthesis because glutathione peroxidase 3 and TXNRD1 expression and TXNRD1 enzyme activity were restored. Consistently, selenium depleted ROS levels downstream of NOX4 induction. Collectively, this work demonstrates that dysregulated redox homeostasis driven by elevated NOX4-derived ROS signaling underlies fibroblast-to-myofibroblast differentiation in the diseased prostatic stroma. Further, these data indicate the potential clinical value of selenium and/or NOX4 inhibitors in preventing the functional pathogenic changes of stromal cells in BPH and PCa.
基质重塑，尤其是成纤维细胞向肌成纤维细胞的分化，是良性前列腺增生（BPH）和实体瘤（包括前列腺癌（PCa））的一个标志。局部转化生长因子β1（TGFβ1）产生增加被认为是诱导刺激因素。鉴于基质重塑积极促进BPH/PCa的发展，人们对开发针对基质的疗法有相当大的兴趣。对用TGFβ1诱导经历成纤维细胞向肌成纤维细胞分化的原代人前列腺基质细胞进行微阵列和定量PCR分析，结果显示活性氧（ROS）产生者烟酰胺腺嘌呤二核苷酸磷酸氧化酶4（NOX4）上调，而含硒的ROS清除酶谷胱甘肽过氧化物酶3、硫氧还蛋白还原酶1（TXNRD1）以及硒转运蛋白硒蛋白P血浆1下调。一致地，NOX4表达在体内与肌成纤维细胞表型特异性相关，并且在人PCa活检组织的肿瘤相关基质中观察到硒蛋白P血浆1缺失。使用慢病毒介导的NOX4短发夹RNA敲低、药物抑制剂、抗氧化剂和硒，我们证明TGFβ1诱导的源自NOX4的ROS是TGFβ1介导的c-jun氨基末端激酶磷酸化所必需的，而这反过来对于随后的下游细胞骨架重塑至关重要。重要的是，补充硒通过增加ROS清除硒酶的生物合成来抑制分化，因为谷胱甘肽过氧化物酶3和TXNRD1的表达以及TXNRD1酶活性得以恢复。一致地，硒降低了NOX4诱导下游的ROS水平。总体而言，这项工作表明由升高的源自NOX4的ROS信号驱动的氧化还原稳态失调是患病前列腺基质中成纤维细胞向肌成纤维细胞分化的基础。此外，这些数据表明硒和/或NOX4抑制剂在预防BPH和PCa中基质细胞功能致病性变化方面的潜在临床价值。
