Oncogenic Ras modulates p38 MAPK-mediated inflammatory cytokine production in glioblastoma cells

Cancer Biology & Therapy
L MunozT Grewal

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 M...Continue Reading

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Citations

May 27, 2017·Cancer Research and Treatment : Official Journal of Korean Cancer Association·So-Hee AhnYoun-Hee Choi
Mar 15, 2020·Cancers·Athena F PhoaLenka Munoz
Jan 19, 2020·Clinical & Translational Oncology : Official Publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico·X WangX Zhu
Nov 2, 2019·Molecular and Cellular Biochemistry·Bor-Chyuan Su, Jyh-Yih Chen
Oct 16, 2018·Molecular Medicine Reports·Yingjie CaoBicheng Wang
Feb 26, 2019·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·William TomaszewskiJohn H Sampson

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Methods Mentioned

BETA
GTPase
ELISA
transfection
Protein Assay

Software Mentioned

ImageJ
GraphPad
Prism
GraphPad Prism

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