Pancreatic cancer cells express 25-hydroxyvitamin D-1α-hydroxylase and their proliferation is inhibited by the prohormone 25-hydroxyvitamin D3
Pancreatic cancer cells express 25-hydroxyvitamin D-1α-hydroxylase and their proliferation is inhibited by the prohormone 25-hydroxyvitamin D3
复制标题
DOI：
10.1093/carcin/bgh086
复制
发表时间：
2004-06-01
期刊：
影响因子：
4.7
通讯作者：
Koumenis, C
中科院分区：
文献类型：
--
作者：
Schwartz, GG;Eads, D;Koumenis, C
类固醇激素1，25-二羟基维生素D-3，[1，25(OH)(2)D-3，骨化三醇]是维生素D的活性代谢物，对多种恶性肿瘤具有多效性抗肿瘤作用。然而，这种激素的临床应用受到高钙血症的限制。25-羟基维生素D-3是1，25(OH)(2)D-3的前体激素，被酶25-羟基维生素D-1-α-羟基酶[1α(OH)ase]羟化为活性激素。α(OH)酶主要在肾脏中发现，但也在前列腺、结肠和其他组织中表达。用免疫组织化学方法，我们报告了1α(OH)酶在正常胰腺组织和恶性胰腺组织中的高表达。在4个胰腺癌细胞系中也检测到该酶的表达和酶活性。25(OH)D-3对四种胰腺癌细胞中的三种有抑制作用，其抑制作用与细胞周期蛋白依赖性激酶抑制剂p21和p27的诱导水平以及细胞周期在G(1)/S检查点的阻滞有关。25(OH)D-3对稳定转导突变的Ki-ras等位基因的细胞株和具有内源性Ki-ras激活突变的细胞株的生长也有抑制作用，这表明激活的Ki-ras突变并不干扰25(OH)D-3的生长抑制作用，这种突变发生在几乎90%的胰腺癌中。1α(OH)酶在正常和恶性胰腺组织中的表达以及前激素在这些细胞中的抗增殖作用，提示25(OH)D-3可能为胰腺癌的治疗和化学预防提供可能的选择。
The steroid hormone 1,25-dihydroxyvitamin D-3, [1,25(OH)(2)D-3, calcitriol], the active metabolite of vitamin D, exerts pleiotropic antitumor effects against several malignancies. However, the clinical use of this hormone is limited by hypercalcemia. 25-Hydroxyvitamin D-3, the prohormone of 1,25(OH)(2)D-3, is hydroxylated to the active hormone by the enzyme 25-hydroxyvitamin-1-alpha-hydroxylase [1alpha(OH)ase]. 1alpha(OH)ase is found primarily in the kidney, but also is expressed in the prostate, colon and other tissues. Using immunohistochemistry, we report that 1alpha(OH)ase is highly expressed in both normal and malignant pancreatic tissue. Expression of this enzyme and enzymatic activity was also detected in four pancreatic tumor cell lines. 25(OH)D-3 inhibited the growth of three of four pancreatic cell lines in a manner that correlated with the level of induction of the cyclin-dependent kinase inhibitors p21 and p27 and with the induction of cell cycle arrest at the G(1)/S checkpoint. The growth of a cell line stably transfected with a mutant Ki-ras allele and of a second cell line with an endogenous Ki-ras activating mutation was also inhibited by 25(OH)D-3, indicating that activating Ki-Ras mutations, which occur in almost 90% of pancreatic adenocarcinomas, do not interfere with the growth-inhibitory effects of 25(OH)D-3. The expression of 1alpha(OH)ase in normal and malignant pancreatic tissue and the antiproliferative effects of the prohormone in these cells, suggest that 25(OH)D-3 may offer possible therapeutic and chemopreventive options for pancreatic cancer.