ATP7A is a novel target of retinoic acid receptor β2 in neuroblastoma cells
ATP7A is a novel target of retinoic acid receptor β2 in neuroblastoma cells
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DOI：
10.1038/sj.bjc.6604833
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发表时间：
2009-01-13
影响因子：
8.8
通讯作者：
Marshall, G. M.
中科院分区：
文献类型：
--
作者：
Bohlken, A.;Cheung, B. B.;Marshall, G. M.
增加的视黄酸受体β（RAR β（2））基因表达是癌细胞对类维生素A抗癌作用的反应性的标志。此外，低基础或诱导RAR β（2）表达是许多人类癌症的共同特征，表明RAR β（2）可能在缺乏补充类维生素A的情况下作为肿瘤抑制基因。我们先前已经证明RAR β 2低表达是晚期神经母细胞瘤的一个特征。在这里，我们证明了RAR β（2）蛋白的ABC结构域本身足以使RAR β（2）对神经母细胞瘤细胞产生生长抑制作用。ATP 7A，铜外排泵，是一种类维生素A反应基因，通过RAR β的异位过表达而上调（2）。RAR β（2）ABC结构域的异位过表达足以诱导ATP 7A表达，而RAR β（2）siRNA阻断了类维生素A处理的神经母细胞瘤细胞中ATP 7A表达的诱导。ATP7A的强制下调减少了类维生素A处理的神经母细胞瘤细胞的铜流出并增加了细胞活力。铜的补充增强了细胞的生长和减少类维生素A的反应，而铜螯合减少的活力和增殖能力。综上所述，我们的数据表明ATP7A表达受维甲酸受体β的调节，并且它对细胞内铜水平有影响，揭示了类维生素A的抗癌作用与铜代谢之间的联系。
Increased retinoic acid receptor beta (RAR beta(2)) gene expression is a hallmark of cancer cell responsiveness to retinoid anticancer effects. Moreover, low basal or induced RAR beta(2) expression is a common feature of many human cancers, suggesting that RAR beta(2) may act as a tumour suppressor gene in the absence of supplemented retinoid. We have previously shown that low RAR beta(2) expression is a feature of advanced neuroblastoma. Here, we demonstrate that the ABC domain of the RAR beta(2) protein alone was sufficient for the growth inhibitory effects of RAR beta(2) on neuroblastoma cells. ATP7A, the copper efflux pump, is a retinoid-responsive gene, was upregulated by ectopic overexpression of RAR beta(2). The ectopic overexpression of the RAR beta(2) ABC domain was sufficient to induce ATP7A expression, whereas, RAR beta(2) siRNA blocked the induction of ATP7A expression in retinoid-treated neuroblastoma cells. Forced downregulation of ATP7A reduced copper efflux and increased viability of retinoid-treated neuroblastoma cells. Copper supplementation enhanced cell growth and reduced retinoid-responsiveness, whereas copper chelation reduced the viability and proliferative capacity. Taken together, our data demonstrates ATP7A expression is regulated by retinoic acid receptor beta and it has effects on intracellular copper levels, revealing a link between the anticancer action of retinoids and copper metabolism.