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Carcinogenesis, Vol. 23, No. 9, 1411-1417, September 2002
© 2002 Oxford University Press


CANCER BIOLOGY

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

Byung Ju Kim1, Mi-Suk Kim1, Ki-Bae Kim1, Ki-Woo Kim1, Yeon-Mi Hong1, In-Ki Kim1, Han-Woong Lee2 and Yong-Keun Jung1,3

1 Department of Life Science, Kwangju Institute of Science and Technology, 1 Oryong-dong Puk-gu, Kwangju 500-712, Korea and
2 Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea

Tumor necrosis factor (TNF)-{alpha} and TNF-related apoptosis inducing ligand (TRAIL) share a common signaling pathway. Here we show a novel potentiating effect of cadmium on TNF-{alpha}- or TRAIL-mediated cell death via distinct signaling. TNF-{alpha} or TRAIL sensitized otherwise resistant NIH3T3 embryo fibroblast cells to death, when exposed to cadmium. The potentiating effects elicited by TNF-{alpha} or TRAIL on cell death were NF-{kappa}B- and SAPK/JNK-independent and were not diminished by the expression of Bcl-2. TNF-{alpha} potentiated the cadmium-induced accumulation of p53 but did not affect expression levels of Bax, Mdm2 and p21WAF/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-{alpha} and cadmium was attenuated by transient expression of a dominant negative p53Val135 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 p53Val135 mutant did not reduce TRAIL- and cadmium-mediated cell death. Taken together, these results suggest that TNF-{alpha} and TRAIL potentiate the cadmium-mediated cell death via distinct p53 expression patterns.


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