Background. Glioma 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. Methods. Active 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. Results. Eighty-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. Conclusions. The 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.
Radiotherapy is a major component of standard-of-care treatment for gliomas, the most prevalent type of brain tumor. However, resistance to radiotherapy remains a major concern. Identification of mechanisms governing radioresistance in gliomas could reveal improved therapeutic strategies for treating patients. Here, we report that mitochondrial metabolic pathways are suppressed in radioresistant gliomas through integrated analyses of transcriptomic data from glioma specimens and cell lines. Decreased expression of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α), the key regulator of mitochondrial biogenesis and metabolism, correlated with glioma recurrence and predicted poor prognosis and response to radiation therapy of glioma patients. The subpopulation of glioma cells with low-mitochondrial-mass exhibited reduced expression of PGC-1α and enhanced resistance to radiation treatment. Mechanistically, PGC-1α was phosphorylated at serine (S) 636 by DNA-dependent protein kinase (DNA-PK) in response to irradiation. Phosphorylation at S636 promoted the degradation of PGC-1α by facilitating its binding to the E3 ligase RNF34. Restoring PGC-1α activity with expression of PGC-1α S636A, a phosphorylation-resistant mutant, or a small molecule PGC-1α activator ZLN005 increased radiosensitivity of resistant glioma cells by reactivating mitochondria-related ROS production and inducing apoptotic effects both in vitro and in vivo. In summary, this study identified a self-protective mechanism in glioma cells in which radiation-induced degradation of PGC-1α and suppression of mitochondrial biogenesis play a central role. Targeted activation of PGC-1α could help improve response to radiation therapy in glioma patients.
<p>Table S7. Clinical information of 95 GBM patients</p>
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