DOWN-MODULATION OF C-MYC EXPRESSION BY INTERFERON-GAMMA AND TUMOR-NECROSIS-FACTOR-ALPHA PRECEDES GROWTH ARREST IN HUMAN-MELANOMA CELLS

After in vitro incubation of melanoma tumour cells Cmel453A with either recombinant interferon gamma (rIFN-gamma) or tumour necrosis factor alpha (rTNF-alpha) a dose-dependent inhibition of cell growth occurred; when both cytokines were added, a synergistic action was observed. Inhibition of DNA synthesis, as measured by [H-3] thymidine incorporation, occurred after 6 h of incubation with rIFN-gamma or rTNF-alpha, and this action was potentiated when the two cytokines were applied simultaneously. Within 1 h, the level of c-myc mRNA in tumour cells had already decreased by, respectively, 60% (S.D. 7) and 25% (S.D. 7); the combined addition of the cytokines resulted in a greater reduction of c-myc mRNA than by each cytokine alone. Downregulation of c-myc expression is an early event, occurring hours before the actual inhibition of outgrowth. Thus, in melanoma cells like Cmel with a high constitutive expression of the c-myc oncogene, the antiproliferative action of rIFN-gamma and rTNF-alpha may be mediated by an inhibition of the expression of c-myc.