Spriggs D, Imamura K, Rodriguez C, Horiguchi J, Kufe D W
Proc Natl Acad Sci U S A. 1987 Sep;84(18):6563-6. doi: 10.1073/pnas.84.18.6563.
Tumor necrosis factor (TNF) is a polypeptide cytokine that is cytotoxic to some but not all tumor cells. The basis for resistance to the cytotoxic effects of this agent remains unclear. We have studied the development of TNF resistance in human ZR-75-1 breast carcinoma cells. ZR-75-1 cells have undetectable levels of TNF RNA and protein. However, TNF transcripts are transiently induced in these cells by exposure to recombinant human TNF. This induction of TNF RNA is associated with production of TNF-like protein in cell lysates and culture supernatants. Stable resistance to TNF-induced cytotoxicity develops when ZR-75-1 cells are exposed to increased concentrations of TNF. The TNF-resistant cells, designated ZR-75-1R, continuously express TNF transcripts and a TNF-like protein. Furthermore, ZR-75-1R cell supernatants contain cytotoxic activity that is abrogated by polyclonal antibody against TNF. The ZR-75-1R cells also possess TNF receptors that are occupied or down-regulated by the TNF-like protein. These findings thus suggest that (i) TNF induces TNF transcripts and production of a TNF-like protein in ZR-75-1 cells and (ii) resistance to TNF-induced cytotoxicity is associated with stable TNF expression.
肿瘤坏死因子（TNF）是一种多肽细胞因子，对部分而非全部肿瘤细胞具有细胞毒性。对该因子细胞毒性作用产生抗性的基础尚不清楚。我们研究了人ZR-75-1乳腺癌细胞中TNF抗性的发展情况。ZR-75-1细胞中未检测到TNF RNA和蛋白质水平。然而，通过暴露于重组人TNF，这些细胞中可短暂诱导出TNF转录本。TNF RNA的这种诱导与细胞裂解物和培养上清液中TNF样蛋白的产生相关。当ZR-75-1细胞暴露于浓度增加的TNF时，会产生对TNF诱导的细胞毒性的稳定抗性。耐TNF细胞，命名为ZR-75-1R，持续表达TNF转录本和一种TNF样蛋白。此外，ZR-75-1R细胞上清液含有细胞毒性活性，该活性可被抗TNF多克隆抗体消除。ZR-75-1R细胞还具有被TNF样蛋白占据或下调的TNF受体。因此，这些发现表明：（i）TNF在ZR-75-1细胞中诱导TNF转录本并产生TNF样蛋白；（ii）对TNF诱导的细胞毒性的抗性与稳定的TNF表达相关。
