Cadmium induces cytotoxicity in human bronchial epithelial cells through upregulation of eIF5A1 and NF-kappaB.
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 significantly upregulate the protein levels of eukaryotic translation initiation factor 5A1 (eIF5A1) and redox-sensitive transcription factor NF-κB p65. 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 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-κB might likely modulate eIF5A1 gene expression. Notably, by bioinformatic analysis, several potential NF-κB binding sites on the upstream promoter region of eIF5A1 gene can be found. Subsequent chromatin immunoprecipitation assay revealed that indeed there is enhanced NF-κB 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-κB in human lung cells.
Laboratory of Cancer Biology and Epigenetics, Shantou University Medical College, Shantou, Guangdong 515041, China; Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong 515041, China.
De-Ju
DJ
Chen
Laboratory of Cancer Biology and Epigenetics, Shantou University Medical College, Shantou, Guangdong 515041, China; Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong 515041, China.
Yan-Ming
YM
Xu
Laboratory of Cancer Biology and Epigenetics, Shantou University Medical College, Shantou, Guangdong 515041, China; Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong 515041, China.
Ji-Ying
JY
Du
Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong 515041, China.
Dong-Yang
DY
Huang
Laboratory of Cancer Biology and Epigenetics, Shantou University Medical College, Shantou, Guangdong 515041, China; Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong 515041, China. Electronic address: andytylau@stu.edu.cn.
Andy T Y
AT
Lau
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D015153:Blotting, Western; D001980:Bronchi / Q000166:cytology; D002104:Cadmium / Q000494:pharmacology*; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002843:Chromatin / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D010448:Peptide Initiation Factors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D040901:Proteomics / Q000379:methods; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*; D000097574:Eukaryotic Translation Initiation Factor 5A
D002104:Cadmium; D002843:Chromatin; D016328:NF-kappa B; D010448:Peptide Initiation Factors; D016601:RNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D000097574:Eukaryotic Translation Initiation Factor 5A
BEAS-2B; Cadmium; Cell death; NF-kappaB; eIF5A1