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IFN-β induces serine phosphorylation of Stat-1 in Ewing's sarcoma cells and mediates apoptosis via induction of IRF-1 and activation of caspase-7

Oncogene volume 19, pages 3372–3383 (2000)Cite this article

Abstract

Four human cell lines derived from Ewing's sarcoma, EW-7, EW-1, COH and ORS, were investigated to establish the effects of human recombinant interferon-α2a and human recombinant interferon-β on cell proliferation and apoptosis. All four cell lines were much more sensitive to the antiproliferative effects of IFN-β than of IFN-α. Analysis of the early signals triggered by IFN-α and IFN-β demonstrated that the two IFNs were similarly effective in inducing tyrosine phosphorylation of the Jak-1 and Tyk-2 kinases and the transcription factors Stat-1 and Stat-2. Interestingly, an additional rapid phosphorylation of Stat-1 on serine was observed after IFN-β treatment, with concomitant activation of p38 mitogen-activated protein kinase. In these cells, Stat-1 Ser727 phosphorylation in response to IFN-β was found to be impaired by p38 MAPkinase inhibitor (SB203580). IFN-β induced the formation of the Interferon Stimulated Gene Factor 3 complex more efficiently than IFN-α, as well as sustained induction of IRF-1, which may account for its greater induction of 2′5′oligo(A)synthetase and greater inhibition of cell proliferation. IFN-β, but not IFN-α, induced apoptosis in wild-type p53 EW-7 and COH cell lines, but not in the mutated p53 EW-1 or ORS cell lines. The apoptosis induced by IFN-β in EW-7 and COH cell lines appeared to be mediated by IRF-1 and involved the activation of caspase-7. Ectopic expression of IRF-1 induced apoptosis in all four cell lines which correlated with the activation of caspase-7 and with the downregulation of the Bcl-2 oncoprotein, as observed for IFN-β-induced apoptosis in parental EW-7 and COH cell lines.

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Acknowledgements

The authors would like to thank Hoffman La Roche (Basel, Switzerland) for the gift of human IFN-α2a, and Drs Furamo Silvano and Arnaud Ythier (ARET-Serono International, Geneva, Switzerland) for the gift of a human IFN-β. We thank Professor Gilbert Lenoir for providing ET cell lines used in this study, and Dr Philippe Benech for providing 2′5′oligo(A)synthetase promoter. We are grateful to Delphine Javelaud for nuclear fragmentation evaluations and to Catherine Silvestri for valuable technical assistance. This work was supported by grants from the Institut National Scientifique et de la Recherche Médicale (INSERM), the Association pour le Recherche contre le Cancer (ARC) and the Ligue Nationale contre le Cancer.

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Authors and Affiliations

  1. INSERM U 365, Institut Curie, Section Recherche, 26, rue d'Ulm, Paris, cedex 05, 75248, France

    Josiane Sancéau & Juana Wietzerbin

  2. Lady Davis Institute for Research, McGill University, Montreal, H3T 1E2, Quebec, Canada

    John Hiscott

  3. INSERM U 509, Institut Curie, Section Recherche, 26, rue d'Ulm, Paris, cedex 05, 75248, France

    Olivier Delattre

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Sancéau, J., Hiscott, J., Delattre, O. et al. IFN-β induces serine phosphorylation of Stat-1 in Ewing's sarcoma cells and mediates apoptosis via induction of IRF-1 and activation of caspase-7. Oncogene 19, 3372–3383 (2000). https://doi.org/10.1038/sj.onc.1203670

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