1. Nociceptin/orphanin FQ antagonizes lipopolysaccharide-stimulated proliferation, migration and inflammatory signaling in human glioblastoma U87 cells.
- Author
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Bedini A, Baiula M, Vincelli G, Formaggio F, Lombardi S, Caprini M, and Spampinato S
- Subjects
- Apoptosis drug effects, Astrocytes drug effects, Astrocytes immunology, Astrocytes metabolism, Astrocytes pathology, Calcium Signaling drug effects, Cell Line, Tumor, Cell Movement drug effects, Cell Proliferation drug effects, Gene Expression Regulation, Neoplastic, Glioblastoma immunology, Glioblastoma metabolism, Glioblastoma pathology, Humans, Interleukin-1beta agonists, Interleukin-1beta antagonists & inhibitors, Interleukin-1beta genetics, Interleukin-1beta metabolism, Intracellular Signaling Peptides and Proteins, Ligands, Lipopolysaccharides antagonists & inhibitors, Lipopolysaccharides toxicity, Neoplasm Proteins agonists, Neoplasm Proteins antagonists & inhibitors, Neoplasm Proteins metabolism, Nerve Tissue Proteins agonists, Nerve Tissue Proteins antagonists & inhibitors, Nerve Tissue Proteins metabolism, RNA Interference, Receptors, Opioid agonists, Receptors, Opioid genetics, TNF Receptor-Associated Factor 6 antagonists & inhibitors, TNF Receptor-Associated Factor 6 genetics, TNF Receptor-Associated Factor 6 metabolism, Toll-Like Receptor 4 agonists, Toll-Like Receptor 4 genetics, Toll-Like Receptor 4 metabolism, beta-Arrestin 2 antagonists & inhibitors, beta-Arrestin 2 genetics, beta-Arrestin 2 metabolism, Nociceptin Receptor, Nociceptin, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Antineoplastic Agents pharmacology, Glioblastoma drug therapy, Opioid Peptides pharmacology, TNF Receptor-Associated Factor 6 agonists, Toll-Like Receptor 4 antagonists & inhibitors, beta-Arrestin 2 agonists
- Abstract
Glioblastoma is among the most aggressive brain tumors and has an exceedingly poor prognosis. Recently, the importance of the tumor microenvironment in glioblastoma cell growth and progression has been emphasized. Toll-like receptor 4 (TLR4) recognizes bacterial lipopolysaccharide (LPS) and endogenous ligands originating from dying cells or the extracellular matrix involved in host defense and in inflammation. G-protein coupled receptors (GPCRs) have gained interest in anti-tumor drug discovery due to the role that they directly or indirectly play by transactivating other receptors, causing cell migration and proliferation. A proteomic analysis showed that the nociceptin receptor (NOPr) is among the GPCRs significantly expressed in glioblastoma cells, including U87 cells. We describe a novel role of the peptide nociceptin (N/OFQ), the endogenous ligand of the NOPr that counteracts cell migration, proliferation and increase in IL-1β mRNA elicited by LPS via TLR4 in U87 glioblastoma cells. Signaling pathways through which N/OFQ inhibits LPS-mediated cell migration and elevation of [Ca
2+ ]i require β-arrestin 2 and are sensitive to TNFR-associated factor 6, c-Src and protein kinase C (PKC). LPS-induced cell proliferation and increase in IL-1β mRNA are counteracted by N/OFQ via β-arrestin 2, PKC and extracellular signal-regulated kinase 1/2; furthermore, the contributions of the transcription factors NF-kB and AP-1 were investigated. Independent of LPS, N/OFQ induces a significant increase in cell apoptosis. Contrary to what was observed in other cell models, a prolonged exposure to this endotoxin did not promote any tolerance of the cellular effects above described, including NOPr down-regulation while N/OFQ loses its inhibitory role., (Copyright © 2017 Elsevier Inc. All rights reserved.)- Published
- 2017
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