c-Myc and E1A induced cellular sensitivity to activated NK cells involves cytotoxic granules as death effectors

The contact of natural killer (NK) cells with foreign cells and with certai n virus-infected or tumor cells triggers the cytolytic machinery of NK cell s. This triggering leads to exocytosis of the cytotoxic NK cell granules. T he oncoproteins c-Myc and E1A render cells vulnerable to NK cell mediated c ytolysis yet the mechanisms of sensitization are not well understood. In a model where foreign cells (rat fibroblasts) were cocultured with human IL-2 activated NK cells, we observed that NK cells were capable of efficiently killing their targets only if the cells overexpressed the oncogene c-Myc or E1A. Both the parental and the oncogene expressing fibroblasts similarly t riggered phosphoinositide hydrolysis in the bound NK cells, demonstrating t hat NK cells were cytolytically activated in contact with both resistant pa rental and oncogene expressing sensitive target fibroblasts. The cell death was independent of mild-type p53 and was not inhibited by an anti-apoptoti c protein E1B19K. These results provided evidence that c-Myc and E1A activa ted the NK cell induced cytolysis at a post-triggering stage of NK cell-tar get cell interaction. In consistence, the c-Myc and E1A overexpressing fibr oblasts were more sensitive to the cytolytic effects of isolated NK cell-de rived granules than parental cells. The data indicate that oncogenes activa te the cytotoxicity of NK cell granules. This mechanism can have a role in directing the cytolytic action of NK cells towards the virus-infected and c ancer cells.