Nickel decreases cellular iron level and converts cytosolic aconitase to iron-regulatory protein 1 in A549 cells
Nickel decreases cellular iron level and converts cytosolic aconitase to iron-regulatory protein 1 in A549 cells
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DOI：
10.1016/j.taap.2004.11.011
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发表时间：
2005-08-15
影响因子：
3.8
通讯作者：
Costa, M
中科院分区：
文献类型：
--
作者：
Chen, HB;Davidson, T;Costa, M
镍（Ni）化合物是公认的致癌物，已知可通过缺氧诱导因子-1 α（HIF-1 α）的稳定和反式激活来启动细胞的缺氧反应。这种变化可能是镍干扰几种Fe（II）依赖性酶的功能的结果。在这项研究中，可溶性镍暴露对细胞铁稳态的影响进行了研究。镍处理A549细胞的线粒体和胞浆乌头酸酶（c-aconitase）的活性下降。胞浆乌头酸酶被转化为铁调节蛋白1，一种对调节细胞铁稳态至关重要的形式。镍暴露后铁调节蛋白I的活性增加稳定和增加转铁蛋白受体（Tfr）mRNA和拮抗铁诱导的铁蛋白轻链蛋白合成。镍处理后乌头酸酶活性的降低既不反映镍对乌头酸酶功能的直接干扰，也不反映镍对[4Fe-4S]簇重构的阻碍。暴露于可溶性镍的A549细胞减少约40%的总细胞铁，减少可能导致所观察到的乌头酸酶活性的降低和铁调节蛋白I活性的增加。铁处理逆转了镍对胞浆乌头酸酶和铁调节蛋白1的影响。为了评估观察到的效应的机制，将过表达二价金属转运蛋白-1（DMT 1）的人胚肾（HEK）细胞与仅表达内源性转运蛋白的A549细胞进行比较，以抑制镍对铁的摄取。抑制数据表明，镍可以通过DMTI进入，并与铁竞争进入细胞。镍对细胞铁稳态的这种干扰可能对细胞调节各种细胞功能的能力产生很大影响，并在正常氧张力下在细胞中产生缺氧状态。这些效应可能在镍如何施加表型选择压力以将正常启动的细胞转化为癌细胞中非常重要。(c)2004年爱思唯尔公司All rights reserved.
Nickel (Ni) compounds are well-established carcinogens and are known to initiate a hypoxic response in cells via the stabilization and transactivation of hypoxia-inducible factor-1 alpha (HIF-1 alpha). This change may be the consequence of nickel's interference with the function of several Fe(II)-dependent enzymes. In this study, the effects of soluble nickel exposure on cellular iron homeostasis were investigated. Nickel treatment decreased both mitochondrial and cytosolic aconitase (c-aconitase) activity in A549 cells. Cytosolic aconitase was converted to iron-regulatory protein 1, a form critical for the regulation of cellular iron homeostasis. The increased activity of iron-regulatory protein I after nickel exposure stabilized and increased transferrin receptor (Tfr) mRNA and antagonized the iron-induced ferritin light chain protein synthesis. The decrease of aconitase activity after nickel treatment reflected neither direct interference with aconitase function nor obstruction of [4Fe-4S] cluster reconstitution by nickel. Exposure of A549 cells to soluble nickel decreased total cellular iron by about 40%, a decrease that likely caused the observed decrease in aconitase activity and the increase of iron-regulatory protein I activity. Iron treatment reversed the effect of nickel on cytosolic aconitase and iron-regulatory protein 1. To assess the mechanism for the observed effects, human embryonic kidney (HEK) cells over expressing divalent metal transporter-1 (DMT1) were compared to A549 cells expressing only endogenous transporters for inhibition of iron uptake by nickel. The inhibition data suggest that nickel can enter via DMTI and compete with iron for entry into the cell. This disturbance of cellular iron homeostasis by nickel may have a great impact on the ability of the cell to regulate a variety of cell functions, as well as create a state of hypoxia in cells under normal oxygen tension. These effects may be very important in how nickel exerts phenotypic selection pressure to convert a normal initiated cell into a cancer cell. (c) 2004 Elsevier Inc. All rights reserved.