Tumor necrosis factor induces apoptosis in hepatoma cells by increasing Ca(2+) release from the endoplasmic reticulum and suppressing Bcl-2 expression

Tumor necrosis factor (TNF) plays an import role in the control of apoptosis. The most well known apoptotic pathway regulated by TNF involves the TNFR1-associated death domain protein, Fas-associated death domain protein, and caspase-8. This study examines the mechanism of TNF-induced apoptosis in F...

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Bibliographic Details
Published in:The Journal of biological chemistry 2002-08, Vol.277 (35), p.31381
Main Authors: Kim, Byung-Chul, Kim, Heung-Tae, Mamura, Mizuko, Ambudkar, Indu S, Choi, Kyeong-Sook, Kim, Seong-Jin
Format: Article
Language:English
Subjects:
Animals
Apoptosis - physiology
bcl-X Protein
Calcium - metabolism
Dantrolene - pharmacology
Endoplasmic Reticulum - drug effects
Endoplasmic Reticulum - metabolism
Gene Expression Regulation, Neoplastic - drug effects
Gene Expression Regulation, Neoplastic - physiology
Genes, bcl-2 - drug effects
Kinetics
Liver Neoplasms, Experimental - metabolism
Liver Neoplasms, Experimental - pathology
Proto-Oncogene Proteins c-bcl-2 - genetics
Proto-Oncogene Proteins c-bcl-2 - metabolism
Rats
Transforming Growth Factor beta - pharmacology
Tumor Cells, Cultured
Tumor Necrosis Factor-alpha - pharmacology
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Summary:Tumor necrosis factor (TNF) plays an import role in the control of apoptosis. The most well known apoptotic pathway regulated by TNF involves the TNFR1-associated death domain protein, Fas-associated death domain protein, and caspase-8. This study examines the mechanism of TNF-induced apoptosis in FaO rat hepatoma cells. TNF treatment significantly increased the percentage of apoptotic cells. TNF did not activate caspase-8 but activated caspase-3, -10, and -12. The effect of TNF on the expression of different members of the Bcl-2 family in these cells was studied. We observed no detectable changes in the steady-state levels of Bcl-X(L), Bax, and Bid, although TNF suppresses Bcl-2 expression. Dantrolene suppressed the inhibitory effect of TNF on Bcl-2 expression. TNF induced release of Ca(2+) from the endoplasmic reticulum (ER) that was blocked by dantrolene. Importantly, the expression of Bcl-2 blocked TNF-induced apoptosis and decreased TNF-induced Ca(2+) release. These results suggest that TNF induces apoptosis by a mechanism that involves increasing Ca(2+) release from the ER and suppression of Bcl-2 expression.
ISSN:0021-9258
DOI:10.1074/jbc.M203465200