Cadmium induces cytotoxicity in human bronchial epithelial cells through upregulation of eIF5A1 and NF-kappaB
Cadmium induces cytotoxicity in human bronchial epithelial cells through upregulation of eIF5A1 and NF-kappaB
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镉通过上调 eIF5A1 和 NF-kappaB 诱导人支气管上皮细胞的细胞毒性
DOI：
10.1016/j.bbrc.2014.01.146
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发表时间：
2014-02-28
影响因子：
3.1
通讯作者：
Lau, Andy T. Y.
中科院分区：
文献类型：
--
作者：
Chen, De-Ju;Xu, Yan-Ming;Lau, Andy T. Y.
镉（Cd）和镉化合物广泛分布于环境中，是众所周知的致癌物。在这里，我们报道了在cdcl2暴露的人支气管上皮细胞（BEAS-2B）中，p53水平以时间和剂量依赖的方式急剧下降，这表明所观察到的cd诱导的细胞毒性不可能是由于p53的促凋亡功能。因此，这促使我们通过蛋白质组学方法进一步研究反应性促凋亡因子。有趣的是，我们发现高水平（20或30 μ M）的Cd可以显著上调真核翻译起始因子5A1 （eIF5A1）和氧化还原敏感转录因子NF-kappa B p65的蛋白水平。此外，cd处理的BEAS-2B细胞中NF-kappa B核易位和染色质结合增强。我们还发现，在Cd暴露的细胞中，eIF5A1的小干扰rna特异性敲低可以减弱Cd细胞毒性，这表明eIF5A1在Cd细胞毒性中可能发挥作用。由于eIF5A1被报道与细胞凋亡有关，但其转录调控知之甚少，我们假设NF-kappa B可能调节eIF5A1基因的表达。值得注意的是，通过生物信息学分析，可以在eIF5A1基因上游启动子区域找到几个潜在的NF-kappa B结合位点。随后的染色质免疫沉淀实验显示，cd处理的BEAS-2B细胞的eIF5A1启动子区域的NF-kappa B结合确实增强。综上所述，我们的研究结果首次提出了促凋亡蛋白eIF5A1的调控机制，其水平可能由nf - κ B在人肺细胞中调节。(C) 2014爱思唯尔公司版权所有。
Cadmium (Cd) and Cd compounds are widely-distributed in the environment and well-known carcinogens. Here, we report that in CdCl2-exposed human bronchial epithelial cells (BEAS-2B), the level of p53 is dramatically decreased in a time- and dose-dependent manner, suggesting that the observed Cd-induced cytotoxicity is not likely due to the pro-apoptotic function of p53. Therefore, this prompted us to further study the responsive pro-apoptotic factors by proteomic approaches. Interestingly, we identified that high levels (20 or 30 mu M) of Cd can significantly upregulate the protein levels of eukaryotic translation initiation factor 5A1 (eIF5A1) and redox-sensitive transcription factor NF-kappa B p65. Moreover, there is an enhanced NF-kappa B nuclear translocation as well as chromatin-binding in Cd-treated BEAS-2B cells. We also show that small interfering RNA-specific knockdown of eIF5A1 in Cd-exposed cells attenuated the Cd cytotoxicity, indicating the potential role of eIF5A1 in Cd cytotoxicity. As eIF5A1 is reported to be related with cell apoptosis but little is known about its transcriptional control, we hypothesize that NF-kappa B might likely modulate eIF5A1 gene expression. Notably, by bioinformatic analysis, several potential NF-kappa B binding sites on the upstream promoter region of eIF5A1 gene can be found. Subsequent chromatin immunoprecipitation assay revealed that indeed there is enhanced NF-kappa B binding on eIF5A1 promoter region of Cd-treated BEAS-2B cells. Taken together, our findings suggest for the first time a regulatory mechanism for the pro-apoptotic protein eIF5A1 in which its level is possibly modulated by NF-kappa B in human lung cells. (C) 2014 Elsevier Inc. All rights reserved.