Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Mol Cell Endocrinol. 2011 Aug 6;342(1-2):32-40. doi: 10.1016/j.mce.2011.05.025. Epub 2011 Jun 1.
Parathyroid hormone-related protein (PTHrP) increases the growth and osteolytic potential of prostate cancer cells, making it important to control PTHrP expression. PTHrP expression is suppressed by 1,25-dihydroxyvitamin D(3) (1,25D). The aim of this study was to identify the pathways via which 1,25D exerts these effects. Our main findings are that 1,25D regulates PTHrP levels via multiple pathways in PC-3 and C4-2 (human prostate cancer) cell lines, and regulation is dependent on VDR expression. The human PTHrP gene has three promoters (P); PC-3 cells preferentially utilize P2 and P3, while C4-2 cells preferentially utilize P1. 1,25D regulates PTHrP transcriptional activity from both P1 and P3. The 1,25D-mediated decrease in PTHrP mRNA levels also involves a post-transcriptional pathway since 1,25D decreases PTHrP mRNA stability. 1,25D also suppresses PTHrP expression directly at the protein level by increasing its degradation. Regulation of PTHrP levels is dependent on VDR expression, as using siRNAs to deplete VDR expression negates the 1,25D-mediated downregulation of PTHrP expression. These results indicate the importance of maintaining adequate 1,25D levels and VDR status to control PTHrP levels.
甲状旁腺激素相关蛋白 (PTHrP) 可促进前列腺癌细胞的生长和溶骨性潜能，因此控制 PTHrP 表达至关重要。1,25-二羟维生素 D3（1,25D）可抑制 PTHrP 的表达。本研究旨在确定 1,25D 发挥这些作用的途径。我们的主要发现是，1,25D 通过多种途径调节 PC-3 和 C4-2（人前列腺癌细胞）细胞系中的 PTHrP 水平，并且这种调节依赖于 VDR 表达。人 PTHrP 基因有三个启动子（P）；PC-3 细胞优先利用 P2 和 P3，而 C4-2 细胞优先利用 P1。1,25D 调节 P1 和 P3 上的 PTHrP 转录活性。1,25D 降低 PTHrP mRNA 水平还涉及转录后途径，因为 1,25D 降低了 PTHrP mRNA 的稳定性。1,25D 还通过增加其降解直接在蛋白水平上抑制 PTHrP 的表达。PTHrP 水平的调节依赖于 VDR 的表达，因为使用 siRNA 耗尽 VDR 表达可否定 1,25D 介导的 PTHrP 表达下调。这些结果表明，维持足够的 1,25D 水平和 VDR 状态以控制 PTHrP 水平非常重要。
