Protective role of 1α, 25-dihydroxyvitamin D3 against oxidative stress in nonmalignant human prostate epithelial cells
Protective role of 1α, 25-dihydroxyvitamin D3 against oxidative stress in nonmalignant human prostate epithelial cells
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DOI：
10.1002/ijc.23460
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发表时间：
2008-06-15
影响因子：
6.4
通讯作者：
Lee, Yi-Fen
中科院分区：
文献类型：
--
作者：
Bao, Bo-Ying;Ting, Huei-Ju;Lee, Yi-Fen
通过内源性或外源性来源的活性氧（ROS）的过度产生可诱导DNA损伤，DNA损伤的积累可导致多步骤致癌：流行病学和许多体外和体内实验室研究已经表明维生素D的抗氧化作用。在探索维生素D在前列腺细胞中的抗氧化作用时，我们发现维生素D的活性形式1 α，25-二羟基维生素D（3）（1，25-VD）可以保护非恶性人类前列腺上皮细胞系BPH-1和RWPE-1，但不能保护恶性人类前列腺上皮细胞CWR 22 R和DU 145免受氧化应激诱导的细胞死亡。葡萄糖-6-磷酸脱氢酶（G6 PD）是一种重要的抗氧化酶，1，25-VD可诱导G6 PD的产生，并呈剂量和时间依赖性。使用染色质免疫沉淀（ChIP）分析的机制研究揭示，位于G6 PD基因组的第一内含子中的直接重复序列-3（DR 3）维生素D反应元件可以被配体维生素D受体结合，从而调节G6 PD基因表达。1，25-VD可提高G6 PD活性和谷胱甘肽水平，抑制细胞内ROS的生成。此外，脱氢表雄酮，G6 PD活性的非竞争性抑制剂，取消1，25-VD的保护作用。总之，我们的研究结果表明，1，25-VD可以通过G6 PD活性的转录激活消除ROS诱导的细胞损伤来保护非恶性前列腺细胞免受氧化应激诱导的细胞死亡。维生素D的抗氧化作用加强了其在癌症化学预防中的作用，并增加了维生素D对癌症的有益作用。(C)2008 Wiley-Liss，Inc.
Overproduction of reactive oxygen species (ROS), through either endogenous or exogenous sources, could induce DNA damage, and accumulation of DNA damage might lead to multistep carcinogenesis: The antioxidative effects of vitamin D have been suggested by epidemiological and many in vitro and in vivo laboratory studies. While exploring the antioxidative effects of vitamin D in prostate cells, we found that the active form of vitamin D, 1 alpha, 25-dihydroxyvitamin D(3) (1,25-VD), can protect nonmalignant human prostate epithelial cell lines, BPH-1 and RWPE-1, but not malignant human prostate epithelial cells, CWR22R and DU 145, from oxidative stress-induced cell death. Glucose-6-phosphate dehydrogenase (G6PD), a key antioxidant enzyme, was dose-and time-dependently induced by 1,25-VD. Mechanistic studies using chromatin immunoprecipitation (ChIP) assay revealed that a direct repeat-3 (DR3) vitamin D response element located in the first intron of the G6PD genome can be bound by liganded vitamin D receptor, thereby regulating G6PD gene expression. Increasing G6PD activity and glutathione level by 1,25-VD can scavenge cellular ROS. Moreover, the protective effects of 1,25-VD were abolished by dehydroepiandrosterone, a noncompetitive inhibitor of G6PD activity. Together, our results showed that 1,25-VD can protect nonmalignant prostate cells from oxidative stress-induced cell death by elimination of ROS-induced cellular injuries through transcriptional activation of G6PD activity. The antioxidative effect of vitamin D strengthens its roles in cancer chemoprevention and adds to a growing list of beneficial effects of vitamin D against cancer. (C) 2008 Wiley-Liss, Inc.