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The p38-MK2-HuR pathway potentiates EGFRvIII–IL-1β-driven IL-6 secretion in glioblastoma cells

Oncogene volume 34, pages 2934–2942 (2015)Cite this article

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Abstract

The microenvironment of glioblastoma (GBM) contains high levels of inflammatory cytokine interleukin 6 (IL-6), which contributes to promote tumour progression and invasion. The common epidermal growth factor receptor variant III (EGFRvIII) mutation in GBM is associated with significantly higher levels of IL-6. Furthermore, elevated IL-1β levels in GBM tumours are also believed to activate GBM cells and enhance IL-6 production. However, the crosstalk between these intrinsic and extrinsic factors within the oncogene-microenvironment of GBM causing overproduction of IL-6 is poorly understood. Here, we show that EGFRvIII potentiates IL-1β-induced IL-6 secretion from GBM cells. Importantly, exacerbation of IL-6 production is most effectively attenuated in EGFRvIII-expressing GBM cells with inhibitors of p38 mitogen-activated protein kinase (p38 MAPK) and MAPK-activated protein kinase 2 (MK2). Enhanced IL-6 production and increased sensitivity toward pharmacological p38 MAPK and MK2 inhibitors in EGFRvIII-expressing GBM cells is associated with increased MK2-dependent nuclear–cytoplasmic shuttling and accumulation of human antigen R (HuR), an IL-6 mRNA-stabilising protein, in the cytosol. IL-1β-stimulated activation of the p38 MAPK–MK2-HuR pathway significantly enhances IL-6 mRNA stability in GBM cells carrying EGFRvIII. Further supporting a role for the p38 MAPK–MK2-HuR pathway in the development of inflammatory environment in GBM, activated MK2 is found in more than 50% of investigated GBM tissues and correlates with lower grade and secondary GBMs. Taken together, p38 MAPK–MK2-HuR signalling may enhance the potential of intrinsic (EGFRvIII) and extrinsic (IL-1β) factors to develop an inflammatory GBM environment. Hence, further improvement of brain-permeable and anti-inflammatory inhibitors targeting p38 MAPK, MK2 and HuR may combat progression of lower grade gliomas into aggressive GBMs.

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Acknowledgements

This study was supported by grants from National Foundation for Medical Research and Innovation and the University of Sydney Brown Fellowship to LM. TG acknowledges support from the National Health and Medical Research Council of Australia (510294) and the University of Sydney (2010-02681). GJG is supported by the Australian Research Council (FT120100397) and Tour de Cure. AJA is supported by the National Health and Medical Research Council of Australia (1025637). We would like to thank Maggie Lee for technical assistance with immunohistochemistry and Myriam Gorospe for pHuR(S202) antibody.

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Author notes

  1. F M S Gurgis and Y T Yeung: These authors contributed equally to this work.

Authors and Affiliations

  1. School of Medical Sciences/Pharmacology, University of Sydney, New South Wales, Australia

    F M S Gurgis, Y T Yeung, M X M Tang & L Munoz

  2. Faculty of Pharmacy, University of Sydney, New South Wales, Australia,

    Y T Yeung, A J Ammit & T Grewal

  3. Australian School of Advanced Medicine, Macquarie University, New South Wales, Australia

    B Heng & G J Guillemin

  4. School of Medical Sciences/Pathology, University of Sydney, New South Wales, Australia,

    M Buckland

  5. Department of Pathology and Fimlab laboratories, Tampere University Hospital, Tampere, Finland

    J Haapasalo & H Haapasalo

  6. Tampere University Hospital, Unit of Neurosurgery, Tampere, Finland

    J Haapasalo

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Correspondence to L Munoz.

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Gurgis, F., Yeung, Y., Tang, M. et al. The p38-MK2-HuR pathway potentiates EGFRvIII–IL-1β-driven IL-6 secretion in glioblastoma cells. Oncogene 34, 2934–2942 (2015). https://doi.org/10.1038/onc.2014.225

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  • DOI: https://doi.org/10.1038/onc.2014.225

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