Role of eukaryotic translation initiation factor 4E (eIF4E) in cadmium-induced cytotoxicity and cell death.
Toxicologist 2005 Mar; 84(Suppl 1):239
The role of eukaryotic translation initiation factor 4E (eIF4E), in cadmium-induced cytotoxicity and cell death was investigated. Exposure of human cell lines HCT15, PLC/PR/5, HeLa and Chang, to cadmium chloride (Cd) resulted in a dose-dependent toxicity and death. Western blot analysis of the cells demonstrated a significant inhibition of eIF4E gene (protein) in response to Cd exposure. Whether the inhibition of eIF4E was responsible for the observed toxicity and death was studied by silencing the cellular expression of eIF4E gene by employing a small interfering RNA (SiRNA) specifically targeting the eIF4E gene. The SiRNAmediated silencing of eIF4E gene expression resulted in significant cytotoxicity and cell death suggesting that the cytotoxicity and cell death noticed among the Cdtreated cells were probably due to the chemical-induced inhibition of eIF4E gene expression. Transgenic Chinese hamster ovary cell lines overexpressing eIF4E were resistant to Cd-induced cytotoxicity and cell death. Results of Western blot analysis and immunoprecipitation experiments demonstrated a significant induction of ubiquitination of eIF4E in the Cd treated cells. Pre-exposure of cells to proteasome inhibitors blocked the Cd-induced inhibition of eIF4E gene expression as well as the resulting cytotoxicity and cell death. Furthermore, exposure of cells to Cd resulted in a significant inhibition of expression of the cell cycle and growth regulating gene, cyclin D1. Transfection of cells with SiRNA specifically targeting eIF4E gene expression also resulted in a significant inhibition of cyclin D1 gene expression suggesting that the observed inhibition of cyclin D1 gene in the Cd-treated cells is most likely mediated through inhibition of eIF4E gene. Taken together, our results demonstrate that the exposure of cells to cadmium chloride resulted in cytotoxicity and cell death due to the enhanced ubiquitination and proteolysis and the consequent inhibition of eIF4E gene expression leading to diminished cellular level of critical genes such as cyclin D1.
Cadmium-compounds; Cell-damage; Cytotoxic-effects; Cytotoxicity; Cytotoxins; Exposure-levels; Exposure-assessment; Toxic-effects; Toxins
Research Tools and Approaches: Cancer Research Methods
The Toxicologist. Society of Toxicology 44th Annual Meeting and ToxExpo, March 6-10, 2005, New Orleans, Louisiana