Tovar Sepulveda Veronica A, Falzon Miriam
Department of Pharmacology and Toxicology, Sealy Center for Molecular Science, University of Texas Medical Branch, 10th and Market Streets, Galveston, TX 77555, USA.
Mol Cell Endocrinol. 2003 Jun 30;204(1-2):51-64. doi: 10.1016/s0303-7207(03)00148-5.
Parathyroid hormone-related protein (PTHrP) is expressed by prostate cancer cells. Since PTHrP increases the growth and enhances the osteolytic effects of prostate cancer cells, it is important to control the level of PTHrP expression in these cells. We show that 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and its non-calcemic analogue, EB1089, suppress PTHrP mRNA and protein levels in the human prostate cancer cell lines PC-3 and LNCaP. The human PTHrP gene contains a sequence element homologous to the negative vitamin D response element within the parathyroid hormone gene. This DNA sequence (nVDRE(hPTHrP)) bound the vitamin D receptor (VDR) present in nuclear extracts from both PC-3 and LNCaP cells. However, when cloned upstream of the SV40 promoter and transiently transfected into PC-3 and LNCaP cells, nVDRE(hPTHrP) downregulated promoter activity in response to 1,25(OH)2D3 or EB1089 treatment in LNCaP, but not in PC-3, cells. These results may help to explain why some prostate cancers appear to be refractory to treatment with vitamin D analogues.
甲状旁腺激素相关蛋白（PTHrP）由前列腺癌细胞表达。由于PTHrP可促进前列腺癌细胞的生长并增强其溶骨作用，因此控制这些细胞中PTHrP的表达水平很重要。我们发现，1,25-二羟维生素D3（1,25(OH)2D3）及其非钙调节类似物EB1089可抑制人前列腺癌细胞系PC-3和LNCaP中PTHrP的mRNA和蛋白水平。人PTHrP基因包含一个与甲状旁腺激素基因内负性维生素D反应元件同源的序列元件。该DNA序列（nVDRE(hPTHrP)）可与PC-3和LNCaP细胞的核提取物中存在的维生素D受体（VDR）结合。然而，当克隆到SV40启动子上游并瞬时转染到PC-3和LNCaP细胞中时，nVDRE(hPTHrP)在LNCaP细胞中可响应1,25(OH)2D3或EB1089处理而下调启动子活性，但在PC-3细胞中则不然。这些结果可能有助于解释为什么有些前列腺癌似乎对维生素D类似物治疗无效。
