Soluble nickel inhibits HIF-prolyl-hydroxylases creating persistent hypoxic signaling in A549 cells
Soluble nickel inhibits HIF-prolyl-hydroxylases creating persistent hypoxic signaling in A549 cells
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DOI：
10.1002/mc.20176
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发表时间：
2006-07-01
影响因子：
4.6
通讯作者：
Costa, Max
中科院分区：
文献类型：
--
作者：
Davidson, Todd L.;Chen, Haobin;Costa, Max
可溶性镍化合物对人类具有致癌性，但其致癌机制尚不清楚。暴露于镍的一个主要后果是缺氧诱导因子-1 α（HIF-1 α）的稳定，这是一种已知在多种癌症中过表达的蛋白质。在这项研究中，我们报告了持久稳定的HIF-1 α氯化镍72小时后，从培养基中去除镍。此外，我们表明，HIF-脯氨酰羟化酶（PHD的）被抑制，当细胞暴露于镍，镍被去除后，他们仍然压抑了长达72小时。然后，我们表明，镍可以抑制纯化的HIF-PHD的2在体外，通过直接干扰酶。通过理论计算，我们还表明，镍可能能够取代铁在这种酶的活性位点，提供了一个合理的机制，持久抑制HIF-PHD的镍。所提供的数据表明，镍可以直接干扰HIF-PHD，并且不会通过简单地消耗细胞因子（如铁或抗坏血酸）来抑制酶。了解镍可以抑制HIF-PHD和稳定HIF-1 α的机制可能对癌症和缺血性疾病的治疗很重要。(c)2006 Wiley-Liss，Inc.
Soluble nickel compounds are carcinogenic to humans although the mechanism by which they cause cancer remains unclear. One major consequence of exposure to nickel is the stabilization of hypoxia inducible factor-1 alpha (HIF-1 alpha), a protein known to be overexpressed in a variety of cancers. In this study, we report a persistent stabilization of HIF-1 alpha by nickel chloride up to 72 h after the removal of nickel from the culture media. In addition, we show that the HIF-prolyl hydroxylases (PHD's) are inhibited when cells are exposed to nickel and that they remain repressed for up to 72 h after nickel is removed. We then show that nickel can inhibit purified HIF-PHD's 2 in vitro, through direct interference with the enzyme. Through theoretical calculations, we also demonstrate that nickel may be able to replace the iron in the active site of this enzyme, providing a plausible mechanism for the persistent inhibition of HIF-PHD's by nickel. The data presented suggest that nickel can interfere with HIF-PHD directly and does not inhibit the enzyme by simply depleting cellular factors, such as iron or ascorbic acid. Understanding the mechanisms by which nickel can inhibit HIF-PHD's and stabilize HIF-1 alpha a may be important in the treatment of cancer and ischemic diseases. (c) 2006 Wiley-Liss, Inc.