Resistance to cytolysis by tumor necrosis factor alpha in malignant gynecological cell lines is associated with the expression of protein(s) that prevent the activation of phospholipase A2 by tumor necrosis factor alpha.
Although there are a limited number of cell lines that are sensitive to cytolysis by tumor necrosis factor alpha (TNF alpha), the vast majority are resistant. The analysis of TNF alpha-sensitive cells has shown that phospholipase A2 is activated by TNF alpha in these cells and that the activity of phospholipase A2 is required for their cytolysis. Many cell lines that are resistant to TNF alpha-mediated cytolysis are dependent on the maintenance of protein synthesis for their resistance. We have recently shown that this is also true for TNF alpha-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 alpha only in the presence of protein synthesis inhibitors. Here we show that the TNF alpha-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 alpha in the presence of protein synthesis inhibitors, but more importantly, phospholipase A2 was not activated by TNF alpha unless protein synthesis was inhibited. These results indicate that a protein synthesis-dependent resistance mechanism expressed by these cell lines blocks TNF alpha-mediated cytolysis by preventing the activation of phospholipase A2 by TNF alpha.
Mutch
D G
DG
Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri 63110.
Powell
C B
CB
Kao
M S
MS
Collins
J L
JL
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D004351:Drug Resistance / Q000502:physiology*; D004640:Emetine / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000378:metabolism*; D010051:Ovarian Neoplasms; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054467:Phospholipases A2; D011796:Quinacrine / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*; D002583:Uterine Cervical Neoplasms
D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016718:Arachidonic Acid; D010741:Phospholipases A; D054467:Phospholipases A2; D011796:Quinacrine; D004640:Emetine