TNF‐α mediated MEK–ERK signaling in invasion with putative network involving NF‐κB and STAT‐6: a new perspective in glioma. (16th July 2019)

• Record Type: Journal Article
• Authors: Ramaswamy, Palaniswamy; Goswami, Kalyan; Dalavaikodihalli Nanjaiah, Nandakumar; Srinivas, Dwarakanath; Prasad, Chandrajit
• Is Part Of: Cell biology international. Volume 43:Number 11(2019)
• Page Start: 1257
• Page End: 1266
• Publication Date: 2019-07-16
• Subjects: cytokine -- glioblastoma -- hub -- inflammation -- invasion -- signaling; Cytology -- Periodicals; Cells -- Periodicals; 571.605
• DOI: 10.1002/cbin.11125
• Languages: English
• ISSNs: 1065-6995

Abstract

Abstract: Glioblastoma is the most common malignant primary brain tumor with poor prognosis. Invasion involves pro‐inflammatory cytokines and major signaling hubs. Tumor necrosis factor‐α (TNF‐α) acts as a master switch in establishing an intricate link between inflammation and cancer. The present study attempted to explore the possible implication of MAPK extracellular signaling‐regulated kinase kinase (MEK)–extracellular signaling‐regulated kinase (ERK) signaling pathway and expression of nuclear factor‐κB (NF‐κB), signal transducers and activators of transcription‐6 (STAT‐6), ERK, and phosphorylated‐ERK (p‐ERK) signaling proteins in TNF‐α microenvironment. U0126 and PD98059 were used to inhibit the MEK–ERK1/2 pathway. TNF‐α stimulation enhanced invasion in U87MG, U251MG and patient‐derived primary glioma cells, whereas cell viability was not altered. Matrix metalloproteinase‐2 (MMP‐2) activity was increased only in U251MG glioma cells. These data suggest that TNF‐α microenvironment plays an important role in the invasion of U251MG, U87MG, and patient‐derived primary glioma cells, without any cytotoxic effect. The MMP‐2 activity is differentially regulated by TNF‐α stimulation in these cells. TNF‐α stimulation upregulated the protein expression of ERK‐1, ERK‐2 and also increased the level of p‐ERK1/2. TNF‐α stimulation further upregulated the expression of NF‐κB1, STAT‐6 in tandem with Ras–MEK signaling system in U87MG cells, which emphasized the possible involvement of these signaling hubs in the glioma microenvironment. MEK–ERK inhibitors significantly attenuated the invasion of U87MG cells mediated by the TNF‐α stimulation, probably through their inhibitory impact on p‐ERK1/2 and ERK‐2. This study provides the possible rationale of invasion by glioma cells in a TNF‐α‐induced pro‐inflammatory milieu, which involves direct role of MEK–ERK signaling, with possible implication of NF‐κB and STAT‐6.