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NF-κB-dependent cytokine secretion controls Fas expression on chemotherapy-induced premature senescent tumor cells

Oncogene volume 30, pages 2707–2717 (2011)Cite this article

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Abstract

Induction of a senescent phenotype in tumor cells has been linked to anticancer immune response, however, the molecular mechanisms mediating these phenomenon have not yet been determined. In this study, we present evidence that induction of premature senescence in human cancer cell lines induces Fas expression, and loss of resistance to Fas-induced apoptosis. Triggering of Fas by using the agonistic antibody CH11 or the recombinant ligand APO010, activates an apoptotic pathway responsible for cell death. Secretion of pro-inflammatory cytokines by the senescent cells, particularly TNF-α and IFN-γ, mediates Fas upregulation. Indeed, treatment of proliferating cancer cell lines with TNF-α and IFN-γ, upregulates Fas expression, while blocking TNF-α and IFN-γ by using neutralizing antibodies, decreases Fas expression in senescent cells. We also demonstrate that NF-κB has a central role in controlling the senescence-associated secretory phenotype (SASP) by the premature senescent cells, and that TNF-α and IFN-γ, transcriptionally controlled by NF-κB, are the main mediators of Fas upregulation. Our data suggest the existence of an NF-κB-dependent autocrine loop, mediated by TNF-α and IFN-γ, responsible for expression of Fas on the surface of senescent cells, and for their killing.

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Acknowledgements

Financial support: MIUR #2008CCPKRP to AL; MIUR #2007WJZZR2 to GP

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Authors and Affiliations

  1. Istituto di Endocrinologia ed Oncologia Sperimentale, Naples, Italy

    E Crescenzi & F Pacifico

  2. Dipartimento di Biologia e Patologia Cellulare e Molecolare, ‘Federico II’ University of Naples, Naples, Italy

    A Lavorgna, G Palumbo, S Formisano & A Leonardi

  3. Dipartimento di Internistica Clinica e Sperimentale, Seconda Università di Napoli, Naples, Italy

    R De Palma & E D'Aiuto

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  1. E Crescenzi
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  2. F Pacifico
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  3. A Lavorgna
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  6. G Palumbo
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Correspondence to A Leonardi.

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Crescenzi, E., Pacifico, F., Lavorgna, A. et al. NF-κB-dependent cytokine secretion controls Fas expression on chemotherapy-induced premature senescent tumor cells. Oncogene 30, 2707–2717 (2011). https://doi.org/10.1038/onc.2011.1

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  • DOI: https://doi.org/10.1038/onc.2011.1

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