DNA-damaging reagents induce apoptosis through reactive oxygen species-dependent Fas aggregation

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Abstract
DNA-damaging reagents may kill tumor cells through the generation of reactive oxygen species (ROS). Cytotoxic reagents may also induce apoptosis of cancer cells in Fas–FADD-dependent manners. In this study, we explored the possible link between these two apparently distinct pathways in T leukemia cell Jurkat. Our results demonstrated that -irradiation, similar to cisplatin, induced apoptosis by triggering Fas aggregation and activating FADD-caspase-8 apoptotic cascade. The absence of caspase-8 or Fas greatly reduced the sensitivity to apoptosis mediated by DNA-damaging agents. In addition, apoptosis induced by cisplatin and -irradiation, but not by Fas, was inhibited by ROS scavengers, including N-acetyl cysteine, MnTBAP, and C60. Importantly, these ROS scavengers effectively prevented the clustering of Fas receptor induced by cisplatin and -irradiation. Our results suggest that cisplatin and -irradiation promote ROS production, which in turn contributes to Fas receptor aggregation and cell death. The novel coupling between ROS and Fas clustering likely plays a significant role in apoptosis triggered by DNA-damaging reagents in Fas-expressing leukemia cells.