Resistance to Cytolysis by Tumor Necrosis Factor α in Malignant Gynecological Cell Lines Is Associated with the Expression of Protein(s) That Prevent the Activation of Phospholipase A2 by Tumor Necrosis Factor α

Although there are a limited number of cell lines that are sensitive to cytolysis by tumor necrosis factor α (TNFα), the vast majority are resistant. The analysis of TNFα-sensitive cells has shown that phospholipase A2 is activated by TNFα in these cells and that the activity of phospholipase A2 is required for their cytolysis. Many cell lines that are resistant to TNFα-mediated cytolysis are dependent on the maintenance of protein synthesis for their resistance. We have recently shown that this is also true for TNFα-resistant cell lines derived from cervical (ME-180 and SiHa) and ovarian (SK-OV-3 and OVCAR-3) carcinomas, in that they are sensitive to cytolysis by TNFα only in the presence of protein synthesis inhibitors. Here we show that the TNFα-mediated cytolysis of these resistant cell lines in the presence of the protein synthesis inhibitor emetine is similar to that of sensitive cells, in that cytolysis is inhibited by the inhibitors of phospholipase A2. The measurement of the release of radiolabeled material from cervical and ovarian carcinoma cell lines prelabeled with [3H]arachidonic acid showed that not only was phospholipase A2 required for the cytolysis of these cells by TNFα In the presence of protein synthesis inhibitors, but more importantly, phospholipase A2 was not activated by TNFα unless protein synthesis was inhibited. These results indicate that a protein synthesis-dependent resistance mechanism expressed by these cell lines blocks TNFα-mediated cytolysis by preventing the activation of phospholipase A2 by TNFα.