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

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri 63110

Although there are a limited number of cell lines that are sensitive to cytolysis by tumor necrosis factor (TNF), the vast majority are resistant. The analysis of TNF-sensitive cells has shown that phospholipase A₂ is activated by TNF in these cells and that the activity of phospholipase A₂ is required for their cytolysis. Many cell lines that are resistant to TNF-mediated cytolysis are dependent on the maintenance of protein synthesis for their resistance. We have recently shown that this is also true for TNF-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 TNF only in the presence of protein synthesis inhibitors. Here we show that the TNF-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 TNF in the presence of protein synthesis inhibitors, but more importantly, phospholipase A₂ was not activated by TNF unless protein synthesis was inhibited. These results indicate that a protein synthesis-dependent resistance mechanism expressed by these cell lines blocks TNF-mediated cytolysis by preventing the activation of phospholipase A₂ by TNF.

¹ Supported by American Cancer Society Career Development Award (1990–1993).

² Current address: University of California at San Francisco, Division of Gynecologic Oncology, 350 Parnassus Avenue, Suite 300, San Francisco, CA 94117.

³ To whom requests for reprints should be addressed, at: Department of Obstetrics and Gynecology, Washington University School of Medicine, 4911 Barnes Hospital Plaza, St. Louis, MO 63110.

Received 4/ 8/91. Accepted 11/19/91.

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