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c‐Myc induces cellular susceptibility to the cytotoxic action of TNF‐alpha.
Author(s) -
Klefstrom J.,
Västrik I.,
Saksela E.,
Valle J.,
Eilers M.,
Alitalo K.
Publication year - 1994
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1002/j.1460-2075.1994.tb06879.x
Subject(s) - biology , cytotoxic t cell , tumor necrosis factor alpha , microbiology and biotechnology , alpha (finance) , cancer research , immunology , genetics , in vitro , medicine , construct validity , nursing , patient satisfaction
Tumor necrosis factor‐alpha (TNF) is a multifunctional cytokine which is cytotoxic for some tumor cells and transformed cells. The molecular mechanisms which render transformed and tumor cells sensitive to the cytotoxic action of TNF are unclear. We show here that an increased expression of the c‐Myc oncoprotein strongly increases cellular sensitivity to TNF cytotoxicity. In Rat1A fibroblasts, which are resistant to TNF, the addition of TNF with a concomitant activation of a hormone‐inducible c‐Myc‐estrogen receptor chimera (MycER) resulted in apoptotic cell death. Similarly, c‐Myc overexpression enhanced the sensitivity of NIH3T3 fibroblasts to TNF‐induced death. The c‐Myc and TNF‐induced apoptosis was inhibited by ectopic expression of the Bcl2 oncoprotein and by the free oxygen radical scavenging enzyme Mn superoxide dismutase. Furthermore, in highly TNF‐sensitive fibrosarcoma cells, antisense c‐myc oligodeoxynucleotides caused a specific inhibition of TNF cytotoxicity. Our results suggest that the deregulation of c‐Myc, which is common in human tumors and tumor cell lines is one reason why these cells are TNF sensitive.