Abstract
STAT1 and STAT3 are the main mediators of the signaling of interferons (IFNs) and of gp130 cytokines, respectively. Neoplastic T lymphocytes frequently become resistant to the IFN-γ/STAT1 apoptotic pathway, often because of the downregulation of the IFN-γR2 receptor chain. Many studies suggest that cross-regulation between different STATs, in particular between STAT1 and STAT3, may profoundly affect cytokine/growth factor signaling. Here, the function of STAT3 in the negative regulation of STAT1 apoptotic pathway was investigated by RNA interference-mediated STAT3 silencing in human malignant T lymphocytes. In STAT3-depleted cells, interleukin (IL)-6 acquired the capacity to induce apoptosis, correlating with prolonged STAT1 activation and the induction of major histocompatibility complex (MHC) class I expression. In contrast, in the absence of STAT3, IFN-γ could slightly enhance apoptosis but its ability to induce MHC class I expression was unchanged. Accordingly, IL-6, but not IFN-γ, could significantly impair the in vivo growth of STAT3-depleted human neoplastic T lymphocytes transplanted into severe combined immunodeficient mice. Therefore, treatment with IL-6 and simultaneous STAT3 silencing may represent a potential therapeutic approach to control the expansion of IFN-γ-unresponsive neoplastic T cells.
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Acknowledgements
This work was supported by grants from Associazione Italiana per la Ricerca sul Cancro (AIRC), Compagnia di San Paolo (special project Oncology), Ministero dell'Istruzione, dell'Università e della Ricerca (MIUR), ex 40% and Fondo per gli Investimenti della Ricerca di Base (FIRB), Ministero della Salute, Progetto integrato Oncologia; Regione Piemonte: Ricerca Industriale e Sviluppo Precompetitivo (ONCOPROT), Ricerca Industriale ‘Converging Technologies’ (BIOTHER), Ricerca Sanitaria Finalizzata, by a fellowship from FIRB (GR).
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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)
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Regis, G., Icardi, L., Conti, L. et al. IL-6, but not IFN-γ, triggers apoptosis and inhibits in vivo growth of human malignant T cells on STAT3 silencing. Leukemia 23, 2102–2108 (2009). https://doi.org/10.1038/leu.2009.139
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DOI: https://doi.org/10.1038/leu.2009.139
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