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

• Published in: Oncogene Vol. 34; no. 22; pp. 2934 - 2942
• Main Authors: Gurgis, F M S, Yeung, Y T, Tang, M X M, Heng, B, Buckland, M, Ammit, A J, Haapasalo, J, Haapasalo, H, Guillemin, G J, Grewal, T, Munoz, L
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.05.2015; Nature Publishing Group
• Subjects: 13/95; 631/80; Apoptosis; Brain cancer; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cell Biology; Cytosol; ELAV Proteins - metabolism; ELAV-Like Protein 1; Epidermal growth factor; Glioblastoma; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Glioblastoma cells; Human Genetics; Humans; HuR protein; IL-1β; Inflammation; Inflammation - genetics; Inflammation - metabolism; Interleukin 6; Interleukin-1beta - pharmacology; Interleukin-6 - secretion; Internal Medicine; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; MAP kinase; MAP Kinase Signaling System - physiology; Medicine; Medicine & Public Health; mRNA stability; Oncology; p38 Mitogen-Activated Protein Kinases - metabolism; Protein kinase; Protein-Serine-Threonine Kinases - metabolism; Proteins; Receptor, Epidermal Growth Factor - pharmacology; short-communication; Signal transduction; Tumor Cells, Cultured; Tumor Microenvironment - drug effects; Tumor Microenvironment - genetics; Tumors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2014.225

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.