Abstract
Abstract 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 μM) of Cd can up-regulate the protein levels of eukaryotic translation initiation factor 5A-1 (eIF-5A-1) and redox-sensitive transcription factor NF-κB p65 in a time- and dose-dependent manner. Moreover, there is an enhanced NF-κB nuclear translocation as well as chromatin-binding in Cd-treated BEAS-2B cells. We also show that small interfering RNA-specific knockdown of eIF-5A-1 in Cd-exposed cells attenuated the Cd cytotoxicity, indicating the potential role of eIF-5A-1 in Cd cytotoxicity. As eIF-5A-1 is reported to be related with cell apoptosis but little is known about its transcriptional control, we hypothesize that NF-κB might likely modulate eIF-5A-1 gene expression. Notably, by bioinformatic analysis, several potential NF-κB binding sites on the upstream promoter region of eIF-5A-1 gene can be found. Subsequent chromatin immunoprecipitation assay revealed that indeed there is enhanced NF-κB binding on eIF-5A-1 promoter region of Cd-treated cells. Taken together, our findings report for the first time a regulatory mechanism for the pro-apoptotic protein eIF-5A-1 in which its level is controlled in an NF-κB-dependent manner. Citation Format: Ji-Ying Du, De-Ju Chen, Yan-Ming Xu, Andy T. Y. Lau. Cadmium induces cytotoxicity in human bronchial epithelial cell in a p53-independent, nuclear factor NF-kappaB-dependent manner. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5131. doi:10.1158/1538-7445.AM2014-5131
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