title: Oncogenic Ras modulates p38 MAPK-mediated inflammatory cytokine production in glioblastoma cells.
abstract: Inflammation is an important factor promoting the progression of glioblastoma. In the present study we examined the contribution of Ras signaling and TNFα/IL-1β cytokines to the development of the glioblastoma inflammatory microenvironment. Enhanced activation of Ras through de-regulated activation of receptor tyrosine kinases, such as EGFR, PDGFR and cMet, is a hallmark of the majority of glioblastomas. Glioblastoma microenvironment contains high levels of TNFα and IL-1β, which mediate inflammation through induction of a local network of cytokines and chemokines. While many studies have focused on Ras- and TNFα/IL-1β-driven inflammation in isolation, little is known about the co-operation between these oncogenic and microenvironment-derived stimuli. Using constitutively active HRasG12V that mimics enhanced Ras activation, we demonstrate that elevated Ras activity in glioblastoma cells leads to up-regulation of IL-6 and IL-8. Furthermore, Ras synergizes with the microenvironment-derived TNFα and IL-1β resulting in amplified IL-6/IL-8 secretion. IL-8 secretion induced by Ras and TNFα/IL-1β is attenuated by inhibitors targeting Erk, JNK and p38 MAPK pathways. IL-6 secretion significantly decreased upon inhibition of JNK and p38 MAPK pathways. Interestingly, although constitutively active HRasG12V does not increase basal or TNFα/IL-1β stimulated p38 MAPK activity, HRasG12V increased the efficacy of the p38 MAPK inhibitor SB203580 to inhibit IL-1β-induced IL-6 secretion. In summary, oncogenic Ras co-operates with the microenvironment-derived TNFα/IL-1β to sustain inflammatory microenvironment, which was effectively attenuated via inhibition of p38 MAPK signaling.
authors.affiliation: a School of Medical Sciences, Discipline of Pathology, The University of Sydney , Australia.
authors.forename: Lenka
authors.initials: L
authors.lastname: Munoz
authors.affiliation: b Faculty of Pharmacy, The University of Sydney , Australia.
authors.forename: Yiu To
authors.initials: YT
authors.lastname: Yeung
authors.affiliation: b Faculty of Pharmacy, The University of Sydney , Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Grewal
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism*; D011905:Genes, ras / Q000235:genetics*; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D016207:Cytokines; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Glioblastoma; IL-6; IL-8; Ras; inflammation; p38 MAPK