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An NF-κB- and Therapy-Related Regulatory Network in Glioma: A Potential Mechanism of Action for Natural Antiglioma Agents.

ABSTRACT: High-grade gliomas are among the most aggressive malignancies, with significantly low median survival. Recent experimental research in the field has highlighted the importance of natural substances as possible antiglioma agents, also known for their antioxidant and anti-inflammatory action. We have previously shown that natural substances target several surface cluster of differentiation (CD) markers in glioma cells, as part of their mechanism of action. We analyzed the genome-wide NF-κB binding sites residing in consensus regulatory elements, based on ENCODE data. We found that NF-κB binding sites reside adjacent to the promoter regions of genes encoding CD markers targeted by antiglioma agents (namely, CD15/FUT4, CD28, CD44, CD58, CD61/SELL, CD71/TFRC, and CD122/IL2RB). Network and pathway analysis revealed that the markers are associated with a core network of genes that, altogether, participate in processes that associate tumorigenesis with inflammation and immune evasion. Our results reveal a core regulatory network that can be targeted in glioblastoma, with apparent implications in individuals that suffer from this devastating malignancy.

SUBMITTER: Vartholomatos E

PROVIDER: S-EPMC9138293 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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An NF-κB- and Therapy-Related Regulatory Network in Glioma: A Potential Mechanism of Action for Natural Antiglioma Agents.

Vartholomatos Evrysthenis E Mantziou Stefania S Alexiou George A GA Lazari Diamanto D Sioka Chrissa C Kyritsis Athanassios A Markopoulos Georgios S GS

Biomedicines 20220419 5

High-grade gliomas are among the most aggressive malignancies, with significantly low median survival. Recent experimental research in the field has highlighted the importance of natural substances as possible antiglioma agents, also known for their antioxidant and anti-inflammatory action. We have previously shown that natural substances target several surface cluster of differentiation (CD) markers in glioma cells, as part of their mechanism of action. We analyzed the genome-wide NF-κB binding ...[more]

PMID: 35625673

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Project description:Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumor; GBM's inevitable recurrence suggests that glioblastoma stem cells (GSC) allow these tumors to persist. Our previous work showed that FOSL1, transactivated by the STAT3 gene, functions as a tumorigenic gene in glioma pathogenesis and acts as a diagnostic marker and potential drug target in glioma patients. Accumulating evidence shows that STAT3 and NF-κB cooperate to promote the development and progression of various cancers. The link between STAT3 and NF-κB suggests that NF-κB can also transcriptionally regulate FOSL1 and contribute to gliomagenesis. To investigate downstream molecules of FOSL1, we analyzed the transcriptome after overexpressing FOSL1 in a PDX-L14 line characterized by deficient FOSL1 expression. We then conducted immunohistochemical staining for FOSL1 and NF-κB p65 using rabbit polyclonal anti-FOSL1 and NF-κB p65 in glioma tissue microarrays (TMA) derived from 141 glioma patients and 15 healthy individuals. Next, mutants of the human FOSL1 promoter, featuring mutations in essential binding sites for NF-κB were generated using a Q5 site-directed mutagenesis kit. Subsequently, we examined luciferase activity in glioma cells and compared it to the wild-type FOSL1 promoter. Then, we explored the mutual regulation between NF-κB signaling and FOSL1 by modulating the expression of NF-κB or FOSL1. Subsequently, we assessed the activity of FOSL1 and NF-κB. To understand the role of FOSL1 in cell growth and stemness, we conducted a CCK-8 assay and cell cycle analysis, assessing apoptosis and GSC markers, ALDH1, and CD133 under varying FOSL1 expression conditions. Transcriptome analyses of downstream molecules of FOSL1 show that NF-κB signaling pathway is regulated by FOSL1. NF-κB p65 protein expression correlates to the expression of FOSL1 in glioma patients, and both are associated with glioma grades. NF-κB is a crucial transcription factor activating the FOSL1 promoter in glioma cells. Mutual regulation between NF-κB and FOSL1 contributes to glioma tumorigenesis and stemness through promoting G1/S transition and inhibiting apoptosis. Therefore, the FOSL1 molecular pathway is functionally connected to NF-κB activation, enhances stemness, and is indicative that FOSL1 may potentially be a novel GBM drug target.

Project description:BackgroundGlioma is the most common primary intracranial tumor in adult patients. Among them, glioblastoma is a highly malignant one with a poor prognosis. Flavonoids are a class of phenolic compounds widely distributed in plants and have many biological functions, such as anti-inflammatory, antioxidant, antiaging, and anticancer. Nowadays, flavonoids have been applied to the therapy of glioma; however, the molecular mechanism underlying the therapeutic effects has not been fully elaborated. This study was carried out to explore the mechanism of selected active flavonoid compounds in treating glioma using network pharmacology and molecular docking approaches.MethodsActive ingredients and associated targets of flavonoids were acquired by using the Traditional Chinese Medicine Database and Analysis Platform (TCMSP) and Swiss TargetPrediction platform. Genes related to glioma were obtained from the GeneCards and DisGeNET databases. The intersection targets between flavonoid targets and glioma-related genes were used to construct protein-protein interaction (PPI) network via the STRING database, and the results were analyzed by Cytoscape software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed and displayed by utilizing the Metascape portal and clusterProfiler R package. Molecular docking was carried out by iGEMDOCK and SwissDock, and the results were visually displayed by UCSF Chimera software.ResultsEighty-four active flavonoid compounds and 258 targets overlapped between flavonoid targets and glioma-related genes were achieved. PPI network revealed potential therapeutic targets, such as AKT1, EGFR, VEGFA, MAPK3, and CASP3, based on their node degree. GO and KEGG analyses showed that core targets were mainly enriched in the PI3K-Akt signaling pathway. Molecular docking simulation indicated that potential glioma-related targets-MAPK1 and HSP90AA1 were bounded more firmly with epigallocatechin-3-gallate (EGCG) than with quercetin.ConclusionsThe findings of this study indicated that selected active flavonoid compounds might play therapeutic roles in glioma mainly through the PI3K-Akt signaling pathway. Moreover, EGCG had the potential antiglioma activity by targeting MAPK1 and HSP90AA1.

Dataset Information

An NF-κB- and Therapy-Related Regulatory Network in Glioma: A Potential Mechanism of Action for Natural Antiglioma Agents.

Publications

An NF-κB- and Therapy-Related Regulatory Network in Glioma: A Potential Mechanism of Action for Natural Antiglioma Agents.

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