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TRAIL is a key target in S-phase slowing-dependent apoptosis induced by interferon-β in cervical carcinoma cells

Oncogene volume 24, pages 2536–2546 (2005)Cite this article

Abstract

Interferon (IFN)-β induces S-phase slowing and apoptosis in human papilloma virus (HPV)-positive cervical carcinoma cell line ME-180. Here, we show that apoptosis is a consequence of the S-phase lengthening imposed by IFN-β, demonstrating the functional correlation between S-phase alteration and apoptosis induction. In ME-180 cells, where p53 function is inhibited by HPV E6 oncoprotein, IFN-β effects on cell cycle and apoptosis occur independently of p53. The apoptosis due to IFN-β is mediated by the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in a manner dependent on the S-phase deregulation. IFN-β appears to increase TRAIL expression both directly at the mRNA level and indirectly by augmenting surface protein levels as a consequence of the induced S-phase cell accumulation. Moreover, the alteration of the S-phase due to IFN-β promotes TRAIL-dependent apoptosis by potentiating cell sensitivity to TRAIL, possibly through induction of a proapoptotic NF-κB activity and TRAIL-R2 receptor expression. Interestingly, IFN-β-induced TRAIL-dependent apoptotic events strongly differ in the requirement of caspase activity. These results show that IFN-β may induce an apoptotic response by deregulating cell cycle. Understanding the linkage between these mechanisms appears to be of primary importance in the search for new IFN-based therapeutic strategies to circumvent cancer disease or improve clinical outcome.

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Acknowledgements

We thank G Blandino, C Gaetano and B Vogelstein for providing the reagents used in this study. We are grateful to Paolo Piccinini, Sabrina Tocchio and Roberto Gilardi for excellent editorial assistance. We also thank Simonetta Rasi for technical help. This work was supported by CNR Agenzia 2000 CNRC008B98_004, Ministero della Salute Progetto Strategico 2002 and Progetti Nazionali MIUR 2002.

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Author notes

  1. Serena Vannucchi and Maria V Chiantore: Both authors contributed equally to the manuscript

Authors and Affiliations

  1. Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità, Rome, Italy

    Serena Vannucchi, Maria V Chiantore, Gianna Fiorucci & Giovanna Romeo

  2. Institute of Molecular Biology and Pathology, National Research Council, Rome, Italy

    Gianna Fiorucci & Giovanna Romeo

  3. Department of Biology, University of ‘Roma Tre’, Rome, Italy

    Zulema A Percario, Stefano Leone & Elisabetta Affabris

Authors
  1. Serena Vannucchi
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  2. Maria V Chiantore
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  3. Gianna Fiorucci
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  4. Zulema A Percario
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  6. Elisabetta Affabris
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  7. Giovanna Romeo
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Correspondence to Giovanna Romeo.

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Vannucchi, S., Chiantore, M., Fiorucci, G. et al. TRAIL is a key target in S-phase slowing-dependent apoptosis induced by interferon-β in cervical carcinoma cells. Oncogene 24, 2536–2546 (2005). https://doi.org/10.1038/sj.onc.1208403

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