Abstract
Interferon alpha (IFNα) is widely used for treatment of melanoma and certain other malignancies. This cytokine as well as the related IFNβ exerts potent anti-tumorigenic effects; however, their efficacy in patients is often suboptimal. Here, we report that inflammatory signaling impedes the effects of IFNα/β. Melanoma cells can secrete pro-inflammatory cytokines that inhibit cellular responses to IFNα/β via activating the ligand-independent pathway for the phosphorylation and subsequent ubiquitination and accelerated degradation of the IFNAR1 chain of type I IFN receptor. Catalytic activity of the p38 protein kinase was required for IFNAR1 downregulation and inhibition of IFNα/β signaling induced by proinflammatory cytokines such as interleukin 1 (IL-1). Activation of p38 kinase inversely correlated with protein levels of IFNAR1 in clinical melanoma specimens. Inhibition of p38 kinase augmented the inhibitory effects of IFNα/β on cell viability and growth in vitro and in vivo. The roles of inflammation and p38 protein kinase in regulating cellular responses to IFNα/β in normal and tumor cells are discussed.
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Acknowledgements
We thank Drs M Gaestel, LM Duncan, RJ Davis, M Herlyn, M May, E Meggers, A Nebreda, J Ninomiya-Tsuji and Z Ronai for reagents. This work was supported by NIH grants CA092900 and CA142425 (to SYF).
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The authors declare no conflict of interest except for Dr DP Baker who is an employee of BiogenIDEC, Inc. and owns stock of this company.
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HuangFu, WC., Qian, J., Liu, C. et al. Inflammatory signaling compromises cell responses to interferon alpha. Oncogene 31, 161–172 (2012). https://doi.org/10.1038/onc.2011.221
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DOI: https://doi.org/10.1038/onc.2011.221
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