C-MYC INDUCES CELLULAR-SUSCEPTIBILITY TO THE CYTOTOXIC ACTION OF TNF-ALPHA

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 ex pression of the c-Myc oncoprotein strongly increases cellular sensitiv ity to TNF cytotoxicity. In Rat1A fibroblasts, which are resistant to TNF, the addition of TNF with a concomitant activation of a hormone-in ducible c-Myc-estrogen receptor chimera (MycER) resulted in apoptotic cell death. Similarly, c-Myc overexpression enhanced the sensitivity o f NIH3T3 fibroblasts to TNF-induced death. The c-Myc and TNF-induced a poptosis was inhibited by ectopic expression of the Bcl2 oncoprotein a nd by the free oxygen radical scavencing enzyme Mn superoxide dismutas e. Furthermore, in highly TNF-sensitive fibrosarcoma cells, antisense c-myc oligodeoxynucleotides caused a specific inhibition of TNF cytoto xicity. Our results suggest that the deregulation of c-Myc, which is c ommon in human tumors and tumor cell lines is one reason why these cel ls are TNF sensitive.