Ruiz-Ruiz C, Muñoz-Pinedo C, López-Rivas A
Instituto de Parasitología y Biomedicina Consejo Superior de Investigaciones Centificas, Granada, Spain.
Cancer Res. 2000 Oct 15;60(20):5673-80.
In this report, we have assessed the role of IFN-gamma as a sensitizing agent in apoptosis mediated by activation of death receptor CD95 in breast tumor cells. Treatment of the tumor cell lines MCF-7 and MDA-MB231 with IFN-gamma significantly facilitated apoptosis induced by CD95 receptor ligation at the plasma membrane, independently of p53 status. In contrast, IFN-gamma treatment did not enhance the apoptotic effect of the DNA-damaging drug, doxorubicin. Analysis of apoptosis regulators indicated that caspase-8 mRNA and protein levels were up-regulated in both of the cell lines after treatment with IFN-gamma. Furthermore, IFN-gamma sensitized MCF-7 and MDA-MB231 cells to CD95-mediated activation of caspase-8, induction of cytochrome c release from mitochondria, and processing of caspase-9. Release of cytochrome c, caspases activation, and apoptosis were prevented in MCF-7 cells overexpressing Bcl-2. Altogether these results indicate that IFN-gamma, maybe through the elevation of caspase-8 levels, sensitizes human breast tumor cells to a death receptor-mediated, mitochondria-operated pathway of apoptosis.
在本报告中，我们评估了γ干扰素作为一种致敏剂在乳腺肿瘤细胞中由死亡受体CD95激活介导的细胞凋亡中的作用。用γ干扰素处理肿瘤细胞系MCF-7和MDA-MB231显著促进了质膜上CD95受体连接诱导的细胞凋亡，这与p53状态无关。相比之下，γ干扰素处理并未增强DNA损伤药物阿霉素的凋亡效应。对凋亡调节因子的分析表明，用γ干扰素处理后，两种细胞系中的半胱天冬酶-8 mRNA和蛋白水平均上调。此外，γ干扰素使MCF-7和MDA-MB231细胞对CD95介导的半胱天冬酶-8激活、细胞色素c从线粒体释放的诱导以及半胱天冬酶-9的加工敏感。在过表达Bcl-2的MCF-7细胞中，细胞色素c的释放、半胱天冬酶的激活和细胞凋亡均被阻止。总之，这些结果表明，γ干扰素可能通过提高半胱天冬酶-8水平，使人乳腺肿瘤细胞对死亡受体介导的、线粒体操作的细胞凋亡途径敏感。
