The Bradykinin-BDKRB1 Axis Regulates Aquaporin 4 Gene Expression and Consequential Migration and Invasion of Malignant Glioblastoma Cells via a Ca2+-MEK1-ERK1/2-NF-κB Mechanism

Abstract

Glioblastoma multiforme (GBM) is the most common form of brain tumor and is very aggressive. Rapid migration and invasion of glioblastoma cells are two typical features driving malignance of GBM. Bradykinin functionally prompts calcium influx via activation of bradykinin receptor B1/B2 (BDKRB1/2). In this study, we evaluated the roles of bradykinin in migration and invasion of glioblastoma cells and the possible mechanisms. Expressions of aquaporin 4 (AQP4) mRNA and protein were upregulated in human glioblastomas. Furthermore, exposure of human U87 MG glioblastoma cells to bradykinin specifically increased levels of BDKRB1. Successively, bradykinin stimulated influx of calcium, phosphorylation of MEK1 and extracellular signal-regulated kinase (ERK)1/2, translocation and transactivation of nuclear factor-kappaB (NF-κB), and expressions of AQP4 mRNA and protein. Concomitantly, migration and invasion of human glioblastoma cells were elevated by bradykinin. Knocking-down BDKRB1 concurrently decreased AQP4 mRNA expression and cell migration and invasion. The bradykinin-induced effects were further confirmed in murine GL261 glioblastoma cells. Therefore, bradykinin can induce AQP4 expression and subsequent migration and invasion through BDKRB1-mediated calcium influx and subsequent activation of a MEK1-ERK1/2-NF-κB pathway. The bradykinin-BDKRB1 axis and AQP4 could be precise targets for treating GBM patients.

Methylpiperidinopyrazole Attenuates Estrogen-Induced Mitochondrial Energy Production and Subsequent Osteoblast Maturation via an Estrogen Receptor Alpha-Dependent Mechanism

“…Then, primary rat osteoblasts were treated with 25, 50, and 100 μM MPP for 24 h or 100 μM MPP for 6, 12, and 24 h. Morphologies of osteoblasts were observed and photographed using an inverted light microscope (Nikon, Tokyo, Japan) as described previously [ 37 ]. Cell survival was analyzed with a trypan blue exclusion method as described previously [ 38 ]. After treatment with MPP, rat calvarial osteoblasts were trypsinized with 0.1% trypsin-ethylenediaminetetraacetic acid (EDTA) (Gibco-BRL).…”

Molecular and Cellular Complexity of Glioma. Focus on Tumour Microenvironment and the Use of Molecular and Imaging Biomarkers to Overcome Treatment Resistance

“…The authors have demonstrated that the bradykinin/BDKRB1 increased the aqp4 expression through BDKRB1 mediated Ca2+ influx, which induces MEK4 phosphorylation and, consequently the downstream ERK1/2-NF-κB induction both in vitro and in vivo in human and murine cells. Overall, these data have suggested the key-role of bradykinin-BDKRB1-aqp4 action on cytoskeleton and morphological changes, as GBM oedema formation and its invasive and migratory power [128].…”

Residual Disease in Glioma Recurrence: A Dangerous Liaison with Senescence

“…NFkB may drive mesenchymal conversion by controlling the expression of genes associated with a mesenchymal program such as Signal Transducer and Activator of Transcription (STAT) 3 and CCAAT-enhancer-binding protein B (C/EBPB) [ 55 ]. NFkB is constitutively activated in glioma stem cell patient lines and GBM mouse models and has an essential role in controlling GBM pathobiology [ 56 , 57 , 58 , 59 ]. Thus, a mesenchymal state enhances GBM migration and therapy resistance, and can, paradoxically, be created in response to chemo-radiotherapy.…”

“…The invasion is possibly mediated through the IL8 activation of NFkB [ 113 ]. Additionally, bradykinin binding to BKR2 both increases intracellular calcium to support cytoskeletal remodeling as well as activates the NFkB pathway to promote migration of GBM cells [ 58 , 109 ]. This suggests that specialized GBM can migrate across blood vessels in response to chemoattractants secreted by endothelial cells.…”