PP60(V-SRC) KINASE OVEREXPRESSION LEADS TO CELLULAR-RESISTANCE TO THEANTIPROLIFERATIVE EFFECTS OF TUMOR-NECROSIS-FACTOR

While some tumor cells are sensitive to the antiproliferative effects of tumor necrosis factor (TNF), others are resistant. The molecular ba sis for cellular resistance to TNF is not completely understood. Previ ously we have shown that transfection of cells with an oncogene HER2/n eulerb B2, a receptor tyrosine kinase, leads to resistance to the anti cellular effects of TNF [(1988) Proc. Natl. Acad. Sci. USA 85, 5102-51 06]. In the present study, we demonstrate that the overexpression of a nother oncogenic tyrosine kinase, pp60(v-src) also induces resistance to TNF In contrast to HER2, however, pp60(v-src) transfection of cells did not lead to down-modulation of TNF receptors but rather to decrea sed intracellular glutathione levels. The pp60(v-src)-induced cellular resistance to TNF could be abrogated by interferon-gamma. Thus, these results indicate that the resistance of certain tumors to TNF may als o be due in part to the overexpression of pp60(v-src) oncogene.