Sensitizing effects of cadmium on TNF-α- and TRAIL-mediated apoptosis of NIH3T3 cells with distinct expression patterns of p53

Tumor necrosis factor (TNF)-α and TNF-related apoptosis inducing ligand (TRAIL) share a common signaling pathway. Here we show a novel potentiating effect of cadmium on TNF-α- or TRAIL-mediated cell death via distinct signaling. TNF-α or TRAIL sensitized otherwise resistant NIH3T3 embryo fibroblast cells to death, when exposed to cadmium. The potentiating effects elicited by TNF-α or TRAIL on cell death were NF-κB- and SAPK/JNK-independent and were not diminished by the expression of Bcl 2. TNF-α potentiated the cadmium-induced accumulation of p53 but did not affect expression levels of Bax, Mdm2 and p21^WAF/CIP. A similar pattern of p53 accumulation was also observed in Balbc/3T3 fibroblasts but not in human tumor cell lines, MCF7 and HeLa cells. The synergistic cell death evoked by TNF-α and cadmium was attenuated by transient expression of a dominant negative p53^Val135 mutant in NIH3T3 cells and was not observed in p53(-/-) mouse embryo fibroblasts, indicating that p53 accumulation appears to contribute to cell death. In contrast, TRAIL did not further increase the cadmium-induced accumulation of p53 despite its potentiation effects on the cadmium-induced cell death. Expression of p53^Val135 mutant did not reduce TRAIL- and cadmium-mediated cell death. Taken together, these results suggest that TNF-α and TRAIL potentiate the cadmium-mediated cell death via distinct p53 expression patterns.