Department of Pharmacology-Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Prostate. 2011 Jun 1;71(8):791-800. doi: 10.1002/pros.21295. Epub 2010 Nov 4.
Phosphatase homologue of tensin (PTEN) is the most commonly mutated gene in prostate cancer. Bone morphogenetic proteins (BMPs) are known to promote differentiation and inhibit proliferation. Previously published reports from other organ systems led us to investigate a mechanistic relationship between PTEN and BMP signaling in prostate epithelial cells.
We analyzed growth rate and PTEN expression in E6, BPH-1, and C4-2B prostate epithelial cells treated with BMP-4. We also treated doxacyclin-inducible PTEN-C4-2B cells with BMP-4 and doxacyclin to determine the effect of BMP on growth and PTEN expression in conditions of increasing PTEN expression. We determined the dependency of BMP-mediated growth inhibition via siRNA knockdown of PTEN expression and BMP treatment. We determined PTEN protein stability by determining the effect of BMP-4 on PTEN protein at time points after treatment with cyclohexamide, a translation inhibitor.
We found that BMP-4 induces PTEN in E6 and BPH-1 cells and reduces proliferation. Knockdown of PTEN attenuated the growth-inhibiting effects of BMP-4 in these cells. BMP-4 had no effect in PTEN-negative C4-2B cells, but doxacyclin-driven PTEN C4-2B cells responded to BMP-4 with enhanced PTEN and growth inhibition. BMP-4 also increased PTEN protein stability.
BMP signaling induces PTEN expression and sustains PTEN protein expression resulting in inhibition of prostate epithelial cell growth. These data are the first to identify a mechanistic linkage between BMP signaling and PTEN in the prostate, both of which are independently identified as tumor suppressors and suggest possible coordinate dysregulation in prostate cancer.
磷酸酶同系物张力蛋白（PTEN）是前列腺癌中最常发生突变的基因。骨形态发生蛋白（BMPs）已知可促进分化并抑制增殖。来自其他器官系统的先前发表的报告促使我们研究前列腺上皮细胞中 PTEN 和 BMP 信号之间的机制关系。
我们分析了 BMP-4 处理的 E6、BPH-1 和 C4-2B 前列腺上皮细胞的生长速度和 PTEN 表达。我们还用 BMP-4 和多西环素处理可诱导表达 PTEN 的多西环素诱导的 PTEN-C4-2B 细胞，以确定 BMP 在增加 PTEN 表达的情况下对生长和 PTEN 表达的影响。我们通过 PTEN 表达的 siRNA 敲低和 BMP 处理来确定 BMP 介导的生长抑制的依赖性。我们通过测定 BMP-4 在用翻译抑制剂环己酰胺处理后不同时间点对 PTEN 蛋白的影响来确定 PTEN 蛋白稳定性。
我们发现 BMP-4 在 E6 和 BPH-1 细胞中诱导 PTEN，并减少增殖。在这些细胞中，PTEN 的敲低减弱了 BMP-4 的生长抑制作用。PTEN 阴性的 C4-2B 细胞中 BMP-4 没有作用，但多西环素驱动的 PTEN C4-2B 细胞对 BMP-4 有反应，表现为 PTEN 增加和生长抑制。BMP-4 还增加了 PTEN 蛋白的稳定性。
BMP 信号诱导 PTEN 表达并维持 PTEN 蛋白表达，从而抑制前列腺上皮细胞生长。这些数据首次确定了前列腺中 BMP 信号和 PTEN 之间的机制联系，两者均被独立鉴定为肿瘤抑制因子，并提示前列腺癌中可能存在协调失调。
