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Type I interferon and TNFα cooperate with type II interferon for TRAIL induction and triggering of apoptosis in SK-N-MC EWING tumor cells

Oncogene volume 23, pages 4911–4920 (2004)Cite this article

Abstract

Ewing's sarcoma is the second most common human bone tumor in childhood. Here, we investigated the sensitivity of the Ewing tumor cell line, SK-N-MC, to the apoptotic effect of type I (IFNα) and type II (IFNγ) interferons and TNFα. We demonstrate that although IFNα and TNFα alone are unable to induce cell death, they act in synergy with IFNγ to induce SK-N-MC cell apoptosis. The synergistic induction of apoptosis correlated with the synergistic induction of TNFα-related apoptosis-inducing ligand (TRAIL) mRNA and TRAIL protein synthesis as well as of TRAIL secretion. Preparations of inducer-free supernatants from SK-N-MC cells stimulated with combinations of cytokines were shown to be cytotoxic for untreated SK-N-MC cells. This cytotoxicity was partially inhibited by addition of TRAILR2/Fc fusion protein, indicating that the secreted TRAIL mediates, at least in part, the apoptotic effect displayed by the supernatants of stimulated SK-N-MC cells. We have shown that the presence of IFNγ is required to allow the sustained expression of IRF1 in SK-N-MC cells stimulated by addition of IFNα or TNFα suggesting that IRF1 plays a role in the synergistic induction of apoptosis by combinations of cytokines. Furthermore, we have shown that inhibition of NF-κB activation contributes to the IFNγ-mediated sensitization to the apoptotic effect of TNFα. To our knowledge, this is the first report showing that interferon/cytokine combinations are able to induce TRAIL gene expression and TRAIL protein synthesis and secretion in Ewing sarcoma-derived cells. We believe that the observations reported here might contribute to the development of alternative new approaches to the treatment of Ewing tumors resistant to conventional therapy.

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Acknowledgements

We are grateful to Dany Rouillard for FACS analysis Dr A. ISRAEL for the (Igκ)3 plasmid and Dr M. Lanotte for the gift of NB4 cells. We thank BioSidus (Buenos Aires, Argentina) for the gift of human Hu-IFNα-2b (Bioferon®), Roussel-Uclaf (Romainville, France) for the gift of human Hu-IFNγ and Boehringer/Ingelheim (Vienna, Austria) for the gift of human TNFα. This work was supported by grants from the Institut National de la Santé et de la Recherche Medicale (INSERM), the Association pour la Recherche Contre le Cancer (ARC grant 4214) and BioSidus (Argentina).

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  1. INSERM U365 Institut Curie, Section Recherche, 26, rue D'Ulm, Paris, Cedex 05, 75 248, France

    Annie Abadie, Françoise Besançon & Juana Wietzerbin

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Correspondence to Juana Wietzerbin.

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Abadie, A., Besançon, F. & Wietzerbin, J. Type I interferon and TNFα cooperate with type II interferon for TRAIL induction and triggering of apoptosis in SK-N-MC EWING tumor cells. Oncogene 23, 4911–4920 (2004). https://doi.org/10.1038/sj.onc.1207614

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