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首页> 外文期刊>Journal of Cellular Physiology >Resistance to 1,25D-induced differentiation in human acute myeloid leukemia HL60-40AF cells is associated with reduced transcriptional activity and nuclear localization of the vitamin D receptor.
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Resistance to 1,25D-induced differentiation in human acute myeloid leukemia HL60-40AF cells is associated with reduced transcriptional activity and nuclear localization of the vitamin D receptor.

机译：抵抗1,25 d-induced分化人类HL60-40AF急性髓系白血病细胞与转录活动减少有关和核本地化的维生素D受体。

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摘要

The anti-neoplastic effects of 1,25-dihydroxyvitamin D(3) (1,25D) are well documented in numerous tumor cell systems and animal models of cancer. However, despite this pre-clinical success, the clinical use of 1,25D is currently impeded by the dose-limiting hypercalcemia, and the risk of development of resistance to 1,25D. In this study, we investigated the mechanism of resistance to 1,25D of HL60-40AF cells, a model of drug-resistant acute myeloid leukemia, derived from HL60 cells by cultivation in the presence of 1,25D. The data indicate that transcriptional activity of vitamin D receptor (VDR) in 40AF cells increases only briefly when the cells are treated with 1,25D, despite greater basal cellular levels of VDR protein in the resistant than in the 1,25D-sensitive cells. Analysis of the 40AF VDR mRNA sequence indicated alterations in the 5' untranslated region (UTR), but coding domain variations were not observed. When resistance to 1,25D-induced differentiation of 40AF cells was reversed by a combination of 1,25D with potentiators of differentiation (plant derived antioxidants and a p38MAPK inhibitor), an increase in the level of nuclear VDR, as well as an increase in CYP24 mRNA expression was observed. These data suggest that decreased ability of 1,25D to induce VDR nuclear localization and the consequent VDR target gene transcription may be an important reason for the resistance of 40AF cells to 1,25D. Further, our data show that VDR localization and phosphorylation can be increased by combining 1,25D with potentiators of differentiation. Analysis of the mechanisms that underlie the reduction and potentiation of 1,25D-mediated changes in VDR activity may lead to the identification of new cellular targets that enhance 1,25D-induced monocytic differentiation. J. Cell. Physiol. 213:816-825. (c) 2007 Wiley-Liss, Inc.
机译：anti-neoplastic的影响1, 25-dihydroxyvitamin D (3) (1,25 D)在很多肿瘤细胞系统和记录动物模型的癌症。临床前成功,临床使用的1,25 d目前由于dose-limiting吗血钙过多,发展的风险抵抗1,25 d。调查的机制抵抗1,25 dHL60-40AF细胞耐药的典范急性髓系白血病,源自HL60细胞通过培养的1,25 d。表明,转录活动的维生素40 D受体(VDR)房颤细胞增加短暂当细胞接受1,25 d,尽管大的基底细胞层次的论述在耐药比蛋白质1,25 d-sensitive细胞。信使rna序列表示改变5 '翻译区(UTR),但编码域没有发现变化。1,25 d-induced 40 af细胞的分化逆转的1,25 d电位器的区别(植物抗氧化剂和p38MAPK抑制剂)增加核VDR的水平,以及CYP24 mRNA表达的增加观察到。能力1,25 d诱导VDR核本地化和随之而来的VDR基因目标转录可能是一个重要的原因电阻40 af细胞1,25 d。数据显示,VDR本地化和可以增加结合磷酸化1,25 d电位器的分化。背后机制的分析减少和增强作用的1,25 d-mediatedVDR活动可能导致的变化新移动目标的识别增强1,25 d-induced单核细胞的分化。j .细胞。Wiley-Liss公司。

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