Journal Article

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

Haapasalo, J, Tang, M X M, Guillemin, G J, Haapasalo, H, Grewal, T, Yeung, Y T, Munoz, L, Buckland, M, Gurgis, F M S, Ammit, A J, Heng, B

2015

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 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 / Glioma / 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