Antagonistic action of novel 1α,25-dihydroxyvitamin D3-26,23-lactone analogs on differentiation of human leukemia cells (HL-60) induced by 1α,25-dihydroxyvitamin D3
Antagonistic action of novel 1α,25-dihydroxyvitamin D3-26,23-lactone analogs on differentiation of human leukemia cells (HL-60) induced by 1α,25-dihydroxyvitamin D3
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DOI：
10.1074/jbc.274.23.16392
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发表时间：
1999-06-04
影响因子：
4.8
通讯作者：
Ishizuka, S
中科院分区：
文献类型：
--
作者：
Miura, D;Manabe, K;Ishizuka, S
我们利用维生素D核受体(VDR)/维生素D响应元件（DRE）介导的基因组作用评估系统，研究了两种新型1 α，25-二羟维生素D-3 (1 α,25（OH)(2)D-3）及其类似物刺激的1 α，25-二羟维生素D-3 （1 α，25-内酯）类似物对人早幼粒细胞白血病细胞（HL-60）分化的影响。我们发现1 α，25-内酯类似物(23S)-25-脱氢-1 α -羟基维生素-d -3-26,23-内酯（TEI-9647）和(23R)-25-脱氢-1 α -羟基维生素- d3 -26,23-内酯（TEI-9648）与VDR的结合比天然的(23S,25R)-1 α,25(OH)(2) d -3-26,23-内酯更强，但即使在高浓度（10(-6)M）下也不诱导细胞分化。有趣的是，1 α,25(OH)(2)D-3诱导的HL-60细胞分化受到TEI-9647和TEI-9648的抑制，而天然内酯对其没有抑制作用。相比之下，TEI-9647或TEI-9648均未阻断视黄酸或12- o - tetradecanoylphorol -13- acetate诱导的HL-60细胞分化。在单独的研究中，TEI-9647 （10(-7) M）被发现是1 α，25(OH)(2)D-3 （10(-8) M）介导的HL-60细胞中p21（WAF1,CIP1）的诱导和COS-7细胞中荧光素酶报告试验的激活的有效拮抗剂，转染了含有大鼠25(OH)D-3-24羟化酶基因DRE和人类VDR cDNA的cDNA。总的来说，结果强烈表明我们的新型1 α，25-1内酯类似物TEI-9647和TEI-9648是1 α，25(OH)(2)D-3作用的特异性拮抗剂，特别是VDR/ re介导的基因组作用。因此，它们代表了作用于核VDR的拮抗剂的第一批例子。
We examined the effects of two novel 1 alpha,25-dihydroxyvitamin D-3-26,23-lactone (1 alpha,25-lactone) analogues on human promyelocytic leukemia cell (HL-60) differentiation using the evaluation system of the vitamin D nuclear receptor (VDR)/vitamin D-responsive element (DRE)-mediated genomic action stimulated by 1 alpha,25-dihydroxyvitamin D-3 (1 alpha,25(OH)(2)D-3) and its analogues. We found that the 1 alpha,25-lactone analogues (23S)-25-dehydro-1 alpha-hydroxyvitamin-D-3-26,23-lactone (TEI-9647), and (23R)-25-dehydro-1 alpha-hydroxyvitamin-D3-26,23-lactone (TEI-9648) bound much more strongly to the VDR than the natural (23S,25R)-1 alpha,25(OH)(2)D-3-26,23-lactone, but did not induce cell differentiation even at high concentrations (10(-6) M). Intriguingly, the differentiation of HL-60 cells induced by 1 alpha,25(OH)(2)D-3 was inhibited by either TEI-9647 or TEI-9648 but not by the natural lactone. In contrast, retinoic acid or 12-O-tetradecanoylphorbol-13- acetate-induced HL-60 cell differentiation was not blocked by TEI-9647 or TEI-9648. In separate studies, TEI-9647 (10(-7) M) was found to be an effective antagonist of both 1 alpha,25(OH)(2)D-3 (10(-8) M) mediated induction of p21(WAF1,CIP1) in HL-60 cells and activation of the luciferase reporter assay in COS-7 cells transfected with cDNA containing the DRE of the rat 25(OH)D-3-24-hydroxylase gene and cDNA of the human VDR. Collectively the results strongly suggest that our novel 1 alpha,25-1actone analogues, TEI-9647 and TEI-9648, are specific antagonists of 1 alpha,25(OH)(2)D-3 action, specifically VDR/DRE-mediated genomic action. As such, they represent the first examples of antagonists, which act on the nuclear VDR.