Silvestrol alleviates glioblastoma progression through ERK pathway modulation and MANBA and NRG-1 expression.

Background: Glioblastoma, a notably malignant tumor within the central nervous system, is distinguished by its aggressive behavior. Silvestrol, a robust inhibitor of the RNA helicase eukaryotic initiation factor 4A (eIF4A), has shown significant potential as an anticancer compound. Yet, the impact of silvestrol on glioblastoma, especially its molecular mechanisms, has not been fully elucidated. Methods: This investigation employed a variety of in vitro assays, such as cell counting kit-8 (CCK-8), clonogenic, 5-ethynyl-2′-deoxyuridine (EDU), wound healing, and flow cytometry, to evaluate cell cycle progression, apoptosis, cell viability, and migration. Western blot analysis was also performed to study the apoptosis and extracellular regulated kinase (ERK) pathways. After the ERK pathway was inhibited, differentially expressed genes (DEGs) in U87 cells were identified, followed by an analysis of target genes using the gene expression profiling interactive analysis (GEPIA) database. Results: Silvestrol significantly suppressed the proliferation, migration, and colony formation of glioma cells. It caused cell cycle arrest and enhanced apoptosis in these cells. Additionally, silvestrol stimulated the ERK pathway, with these effects being reversible by an ERK phosphorylation inhibitor. Transcriptome combined with GEPIA, GSCA, UALCAN, TIMER database screened 4 potential drug targets of silvestrol: chromosome 1 open reading frame 226 (C1ORF226), mannosidase beta A (MANBA), IQ motif and Sec7 domain 2 (IQSEC2), neuregulin 1 (NRG-1). Among them, C1ORF226 was lower risk gene while MANBA, IQSEC2, and NRG-1 were high-risk genes. Furthermore, silvestrol notably reduced MANBA mRNA levels, which could be reversed by inhibiting ERK phosphorylation. Furthermore, silvestrol markedly decreased NRG-1 protein levels, with an additional reduction observed when the ERK pathway was blocked. Conclusion: Silvestrol’s anti-glioma effects are primarily due to the suppression of MANBA expression via the ERK pathway and possibly by hindering the translation of NRG-1 protein, thus reducing its expression. The downregulation of MANBA and NRG-1 proteins may be crucial in hindering glioma development and progression. These results highlight the intricate relationship between the ERK pathway and gene expression regulation in silvestrol’s therapeutic effectiveness against glioma. [ABSTRACT FROM AUTHOR]