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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 γ-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 γ-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 γ-irradiation. Our results suggest that cisplatin and γ-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.

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Abbreviations

CDDP:

cisplatin

DCFCA:

dichlorodihydrofluorescein diacetate

DHE:

dihydroethidium

DN:

dominant negative

FasL:

Fas ligand FLIP. FLICE-inhibitory protein

GFP:

green fluorescence protein

MnSOD:

manganese superoxide dismutase

MnTBAP:

(Mn(III)tetrakis(4-benzoic acid)porphyrin chloride)

NAC:

N-acetyl L-cysteine

PE:

phycoerythrin

PI:

propidium iodide

ROS:

reactive oxygen species

TBHP:

tert-butyl hydrogen peroxide

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Acknowledgements

We thank Dr Shigekazu Nagata for JB6 cells, Dr. Daniel Olive for Jurkat cells, Dr Vishva Dixit for DN-FADD, Dr Gina Costa and Dr Nan-Shih Liao for pGC-IRES-YFP vector, Dr Garry P Nolan for Phoenix-Eco and Jurkat-Eco cells, and Dr Ken Deen for editing the manuscript.

This project was supported by grant NHRI-EX92-9217BI from National Health Research Institute, a grant from Academia Sinica, Taiwan, ROC.

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Authors and Affiliations

  1. Institute of Molecular Biology, Academia Sinica, Taiwan

    Huey-Lan Huang, Li-Wen Fang, Shu-Ping Lu & Ming-Zong Lai

  2. Graduate Institute of Life Science, National Defense Medical School, Taiwan

    Li-Wen Fang & Ming-Zong Lai

  3. Graduate Institute of Microbiology and Immunology,

    Chen-Kung Chou & Ming-Zong Lai

  4. Department of Life Science, National Yang-Ming University, Taiwan

    Chen-Kung Chou

  5. Institute of Chemistry, Academia Sinica, Taipei, ROC, Taiwan

    Tien-Yau Luh

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  1. Huey-Lan Huang
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Correspondence to Ming-Zong Lai.

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Huang, HL., Fang, LW., Lu, SP. et al. DNA-damaging reagents induce apoptosis through reactive oxygen species-dependent Fas aggregation. Oncogene 22, 8168–8177 (2003). https://doi.org/10.1038/sj.onc.1206979

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