Jul 2026· Gene· pp.
150313
· 0 citations· 35 references
Medicine
TL;DR
Targeting PSMB2 suppressed tumor progression and enhanced the therapeutic response to TMZ in vivo, suggesting that PSMB2 may represent a potential therapeutic target for GBM.
Abstract
Glioblastoma multiforme (GBM), a highly aggressive primary brain malignancy, is characterized by its accelerated development, refractoriness to therapy, and dismal prognosis. The proteasome subunit β2 (PSMB2), a catalytic unit of the 20S proteasome, has been linked to tumorigenesis across multiple malignancies; however, its signaling and therapeutic relevance in GBM remains incompletely defined. U87 and U251 GBM cells were engineered to overexpress (OE-PSMB2) or silence (Sh-PSMB2) PSMB2. We assessed the function of PSMB2 in GBM cell proliferation, migration, and related phenotypes, and further examined its association with the PTEN/PI3K/AKT signaling axis at both transcriptomic and protein levels. A xenograft model was conducted in the intracranial setting where the therapeutic efficacy of PSMB2 silencing, when used together with temozolomide (TMZ), was assessed. PSMB2 overexpression stimulated GBM cell proliferation, migration, and invasion, and PSMB2 silencing inhibited these phenotypes and promoted apoptosis. RNA-seq showed that PI3K/AKT pathway was enriched in Sh-PSMB2 cells. Protein-level analysis showed that PSMB2 expression was inversely associated with PTEN abundance and was accompanied by altered PI3K/AKT pathway activity. PSMB2 silencing decreased tumor burden and increased survival in vivo, and the combination of PSMB2 silencing and TMZ produced the greatest therapeutic effect. PSMB2 may function as a tumor-promoting regulator in GBM and is associated with PTEN/PI3K/AKT pathway modulation. Targeting PSMB2 suppressed tumor progression and enhanced the therapeutic response to TMZ in vivo, suggesting that PSMB2 may represent a potential therapeutic target for GBM.
Glioblastoma (GBM) is among the most aggressive primary brain tumors, marked by rapid proliferation, therapeutic resistance, and profound intratumoral heterogeneity. Epigenetic regulators such as lysine-specific demethylase 1A (KDM1A) and histone deacetylase 2 (HDAC2) are aberrantly expressed in resistant GBM subpopulations and strongly correlate with poor clinical outcomes. Here, we assessed the therapeutic potential of MPT0G521, a dual KDM1A/class I HDAC inhibitor, in disrupting epigenetic regulation and cell cycle progression. Bioinformatic analyses of resistance-associated gene profiles (temozolomide and 2 Gy radiation) and single-cell transcriptomic datasets from distinct tumor regions revealed enrichment of KDM1A and HDAC2 in high-cycling GBM clusters, particularly at invasive margins prone to recurrence. Functional assays demonstrated that MPT0G521 potently inhibited proliferation of both parental and temozolomide-resistant GBM cells, inducing G2/M arrest and apoptosis. Transcriptomic profiling further identified significant downregulation of centrosome integrity genes (FSD1, KIFC1), spindle regulators (TUBB, STMN1, KIF2C, KIF15), kinetochore components (AURKB, CDCA8, SPAG5), and G2/M checkpoint mediators (CENPF, MYBL2, CCNF, MYT1, CDC25A), resulting in disrupted mitotic progression. Mechanistically, MPT0G521 increased histone H3 methylation and acetylation, validating its dual inhibitory activity against KDM1A and class I HDACs. Collectively, these findings indicate that MPT0G521 disrupts the G2/M activation and mitotic machinery, thereby suppressing proliferative and resistant GBM subpopulations. This dual epigenetic strategy holds strong promise for overcoming GBM heterogeneity and reducing recurrence.
An-Chih Wu, J. Chuang, Jr-Jiun Liu et al.· Biochemical Pharmacology· 0 citations
Glioblastoma multiforme (GBM) is a highly malignant primary brain tumor that still lacks highly specific and clinically effective molecular targets for GBM treatment. Sorting Nexin 4 (SNX4) is an important regulatory molecule involved in intracellular membrane trafficking, protein sorting, and receptor recycling on the cell membrane. However, the roles and mechanism of action of SNX4 in GBM remain unclear.
RT-qPCR and Western blotting methods were used to measure the expression levels of SNX4 in GBM cell lines and glioma tissue samples from GBM patients. The prognostic role of SNX4 in glioma patients was analyzed by bioinformatic analysis. The roles and underlying mechanism of action of SNX4 in the cell proliferation, cell apoptosis, cell cycle progression, cell migration, and cell invasion of GBM cell lines whose SNX4 gene was silenced or the regulatory pathway of SNX4 was pharmacologically inhibited were examined by the corresponding assays. The role of SNX4 in GBM growth was measured in subcutaneous and intracranial orthotopic tumor models in nude mice. Candidate SNX4-binding small-molecule compounds were discovered by virtual drug screening of a library of small molecule compounds and cell-based drug activity screening.
SNX4 was overexpressed in GBM cell lines and glioma tissue samples from GBM patients measured by RT-qPCR and Western blotting and its high expression was associated with poor prognosis in patients with glioma. SNX4 promoted GBM progression by activating the TGFβ1/Smad signaling pathway in in vitro cell-based assays. Nevertheless, the precise molecular mechanism linking SNX4 to TGFβ receptor trafficking remains to be elucidated. SNX4 also promoted glioma growth in subcutaneous and intracranial orthotopic GBM tumor models in nude mice. Two candidate SNX4-binding small-molecule compounds, G149 and G431, were identified through virtual screening and validated by cell-based assay. Both compounds suppressed GBM growth and were associated with reduced SNX4 expression and inhibition of the TGFβ1/Smad signaling pathway in vitro and in vivo.
Our findings suggest that SNX4 functions as an important regulator of GBM progression, may serve as a potential prognostic biomarker for glioma patients, and may represent a potential therapeutic target.
Zhipeng Yao, Pengcheng Xu, T. Shen et al.· Journal of Translational Med...· 0 citations
Glioma is a highly aggressive brain tumor with poor prognosis and limited therapeutic options. Although temozolomide (TMZ) remains the standard chemotherapeutic agent for glioma, frequent recurrence and the development of therapeutic resistance continue to limit clinical benefit, highlighting the need for new molecular targets and treatment strategies. Here, we identify neuromedin U receptor 2 (NMUR2) as a driver of glioma progression and a potential therapeutic target. NMUR2 expression was markedly elevated in glioma tissues and positively associated with tumor grade. Functional analyses showed that NMUR2 promoted glioma cell proliferation and migration, whereas NMUR2 silencing attenuated these malignant phenotypes. Mechanistically, NMUR2 activated Gαq-dependent Ca²⁺ signaling, leading to STAT5 phosphorylation and subsequent transcriptional upregulation of the cell cycle-associated genes PIM1 and FOXM1. Drug-repurposing screening of 6,331 compounds identified NNC 05-2090 as a candidate NMUR2 antagonist. NNC 05-2090 blocked NMUR2-mediated Gαq/Ca²⁺/STAT5 signaling, which was associated with reduced PIM1 and FOXM1 expression, cell cycle arrest, and suppression of glioma growth in vitro and in vivo. In addition, combination treatment with TMZ produced synergistic anti-tumor effects in glioma models. Collectively, our findings define a previously unrecognized NMUR2/Gαq/STAT5/PIM1-FOXM1 signaling axis in glioma and support pharmacological inhibition of NMUR2 as a potential therapeutic strategy.
Yuna Roh, Taesang Son, Tae-Hee Han et al.· International Journal on Bio...· 0 citations
BACKGROUND
Gliomas are highly aggressive primary brain tumors with a dismal prognosis. Temozolomide (TMZ) serves as the first-line chemotherapeutic agent for glioma patients. However, the clinical efficacy of TMZ is severely limited by the inevitable development of acquired chemoresistance, which ultimately leads to tumor recurrence and treatment failure. Unraveling the molecular mechanisms underlying TMZ resistance is therefore critical for improving glioma prognosis. This study aimed to identify key genes driving TMZ resistance and explore their underlying mechanisms to provide novel therapeutic targets for overcoming this clinical challenge.
METHODS
Differentially expressed genes (DEGs) between TMZ-resistant (LN229TR, U251TR, and U87TR) and TMZ-sensitive glioma cells were screened using GEO datasets. The intersecting DEGs were subjected to protein-protein interaction (PPI) network construction via the STRING database and visualized using Cytoscape software. Hub genes were identified by integrating the results from the Maximal Clique Centrality (MCC) and Density of Maximum Neighborhood Component (DMNC) algorithms. The expression patterns of candidate hub genes were validated in glioma cells, clinical tissues, and the Gene Expression Profiling Interactive Analysis (GEPIA) database. Functional assays, including cell counting kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine, colony formation, transwell, flow cytometry, and sphere formation assays, were performed to evaluate cell viability, proliferation, migration, apoptosis, and stem-like properties in vitro. Furthermore, a subcutaneous xenograft tumor model in mice was established to assess the in vivo therapeutic effects.
RESULTS
A total of 320 intersecting DEGs were extracted from the three cell line groups, and interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) along with 2'-5'-oligoadenylate synthetase like (OASL) were ultimately identified as the core hub genes. IFIT3 was selected for further investigation due to its significant upregulation in both low-grade gliomas and glioblastoma compared to normal brain tissues. Consistently, IFIT3 expression was remarkably elevated in TMZ-resistant glioma tissues and cell lines (P<0.05), which exhibited significantly higher half-maximal inhibitory concentration (IC50) values of TMZ than their sensitive counterparts (P<0.05). Functionally, IFIT3 silencing significantly decreased the IC50 of TMZ (P<0.05), suppressed cell proliferation (P<0.05), migration (P<0.05), and stem-like traits (P<0.05), and induced apoptosis (P<0.05) in resistant glioma cells. Conversely, ectopic IFIT3 expression exerted opposite effects on cell proliferation, migration, and stem-like traits and notably increased the ratios of phosphorylated phosphoinositide 3-kinase (PI3K) to total PI3K and phosphorylated AKT to total AKT (P<0.05); however, these effects induced by IFIT3 overexpression were effectively reversed by the PI3K inhibitor LY294002 (P<0.05). In vivo experiments demonstrated that knocking down IFIT3 expression remarkably reduced tumor volume and weight upon TMZ treatment, accompanied by decreased expression levels of IFIT3, nuclear proliferation marker (Ki-67), and phosphorylated AKT in tumor tissues (P<0.05).
CONCLUSION
IFIT3 overexpression conferred TMZ resistance and promoted multiple malignant phenotypes in gliomas by activating the PI3K/AKT signaling pathway. Clinically, targeting IFIT3 could effectively re-sensitize resistant gliomas to TMZ, thereby offering a novel and actionable strategy to overcome chemoresistance and improve clinical outcomes for glioma patients.
Yi Fan, He Yang, Hai Yu· Behavioural Brain Research· 0 citations
Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide, with limited biomarkers available for early diagnosis and targeted therapy. AKR1B15, a lesser-studied member of the aldo-keto reductase family, shares high sequence similarity with AKR1B10, but its role in HCC remains unclear. Therefore, this study aimed to investigate the biological function of AKR1B15 in HCC and its involvement in oncogenic signaling pathways. Bioinformatic analysis of gene expression datasets and patient tissue samples was used to evaluate AKR1B15 expression and prognostic relevance. Functional assays were conducted following AKR1B15 knockdown, including CCK-8, colony formation, transwell, wound healing, flow cytometry, and xenograft models. Western blotting and immunofluorescence were employed to assess phosphorylation of key signaling molecules. AKR1B15 expression was significantly elevated in HCC tissues and associated with higher pathologic T stage and worse disease-specific survival (P < 0.05). AKR1B15 knockdown inhibited HCC cell proliferation, invasion, and migration (P < 0.01), and promoted apoptosis (P < 0.001). In vivo, AKR1B15 depletion suppressed tumor growth and reduced Ki-67 expression. Mechanistically, silencing AKR1B15 decreased phosphorylation of p53 (Ser15), PI3K (Tyr458/199), AKT (Ser473), mTOR (Ser2448), and E2F1 (S364), indicating inhibition of the p53-PI3K-AKT-mTOR-E2F1 axis. AKR1B15 promotes HCC progression and is associated with activation of the p53-PI3K-AKT-mTOR-E2F1 signaling pathway. It may serve as a novel diagnostic marker and therapeutic target in hepatocellular carcinoma.
Jie Li, Wei-Lai Chen, Pin-Ting Wu et al.· Scientific Reports· 0 citations
Glioblastoma (GBM) is the most aggressive primary brain tumor with limited therapeutic options and extremely poor prognosis. Aberrant activation of the receptor tyrosine kinase MET drives tumor progression, therapeutic resistance, and reduced survival, particularly in the mesenchymal GBM subtype. Given its crucial role in GBM recurrence and progression, we investigated the mechanisms of resistance to MET inhibition using patient-derived glioma-initiating cells (GICs) and orthotopic xenograft mouse models. GICs were treated with the MET inhibitor crizotinib to elucidate the mechanism of adaptive resistance. Prolonged MET inhibition induced a senescent-like phenotype in GICs, associated with downregulation of BNIP3, a mitochondrial protein regulating mitophagy. We showed that BNIP3 downregulation led to activation of mTOR signaling, promoting cellular survival and adaptive resistance. Combining crizotinib with the mTOR inhibitor everolimus effectively suppressed mTOR activity, reduced cell viability, and induced mitochondrial alterations, apoptosis, and necroptosis. In orthotopic GBM xenograft models, combined MET and mTOR inhibition significantly prolonged survival compared with single-agent treatments. Notably, sequential treatment—crizotinib followed by everolimus—further enhanced therapeutic efficacy. These effects were achieved without significant weight loss, supporting tolerability of the treatment regimen. Our findings identify the BNIP3-mTOR axis as a critical mediator of resistance to MET inhibition and demonstrate that combined inhibition of MET and mTOR exhibits significant synergy against GBM.
Yun-Zhan Li, Hanif Khan, Şeyma Demirsoy et al.· International Journal of Mol...· 0 citations
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