title: The p38-MK2-HuR pathway potentiates EGFRvIII-IL-1β-driven IL-6 secretion in glioblastoma cells.
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.
authors.affiliation: School of Medical Sciences/Pharmacology, University of Sydney, New South Wales, Australia.
authors.forename: F M S
authors.initials: FM
authors.lastname: Gurgis
authors.affiliation: 1] School of Medical Sciences/Pharmacology, University of Sydney, New South Wales, Australia [2] Faculty of Pharmacy, University of Sydney, New South Wales, Australia.
authors.forename: Y T
authors.initials: YT
authors.lastname: Yeung
authors.affiliation: School of Medical Sciences/Pharmacology, University of Sydney, New South Wales, Australia.
authors.forename: M X M
authors.initials: MX
authors.lastname: Tang
authors.affiliation: Australian School of Advanced Medicine, Macquarie University, New South Wales, Australia.
authors.forename: B
authors.initials: B
authors.lastname: Heng
authors.affiliation: School of Medical Sciences/Pathology, University of Sydney, New South Wales, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Buckland
authors.affiliation: Faculty of Pharmacy, University of Sydney, New South Wales, Australia.
authors.forename: A J
authors.initials: AJ
authors.lastname: Ammit
authors.affiliation: 1] Tampere University Hospital, Department of Pathology and Fimlab laboratories, Tampere, Finland [2] Tampere University Hospital, Unit of Neurosurgery, Tampere, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Haapasalo
authors.affiliation: Tampere University Hospital, Department of Pathology and Fimlab laboratories, Tampere, Finland.
authors.forename: H
authors.initials: H
authors.lastname: Haapasalo
authors.affiliation: Australian School of Advanced Medicine, Macquarie University, New South Wales, Australia.
authors.forename: G J
authors.identifier: 0000000181054470
authors.initials: GJ
authors.lastname: Guillemin
authors.affiliation: Faculty of Pharmacy, University of Sydney, New South Wales, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Grewal
authors.affiliation: School of Medical Sciences/Pharmacology, University of Sydney, New South Wales, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Munoz
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051959:ELAV Proteins / Q000378:metabolism; D000067780:ELAV-Like Protein 1; D066246:ErbB Receptors / Q000494:pharmacology*; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology*; D015850:Interleukin-6 / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D066246:ErbB Receptors; D053583:Interleukin-1beta; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C098770:ELAVL1 protein, human; C508600:IL6 protein, human; C410723:epidermal growth factor receptor VIII
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