DNA-damaging reagents induce apoptosis through reactive oxygen species-dependent Fas aggregation.
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 gamma-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 gamma-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 gamma-irradiation. Our results suggest that cisplatin and gamma-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.
Huang
Huey-Lan
HL
Institute of Molecular Biology, Academia Sinica, Taiwan.
Fang
Li-Wen
LW
Lu
Shu-Ping
SP
Chou
Chen-Kung
CK
Luh
Tien-Yau
TY
Lai
Ming-Zong
MZ
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects*; D002352:Carrier Proteins / Q000378:metabolism; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage / Q000528:radiation effects*; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; D005720:Gamma Rays; D006801:Humans; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019014:fas Receptor / Q000528:radiation effects*
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D002352:Carrier Proteins; C505533:FADD protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D019014:fas Receptor; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D002945:Cisplatin