The Role and Applied Value of Mitochondria in Glioma‐Related Research

CNS Neuroscience & Therapeutics, Journal Year: 2024, Volume and Issue: 30(12)

Published: Dec. 1, 2024

Mitochondria, known as the "energy factory" of cells, are essential organelles with a double membrane structure and genetic material found in most eukaryotic cells. They play crucial role tumorigenesis development, alterations mitochondrial function tumor cells leading to characteristics such rapid proliferation, invasion, drug resistance. Glioma, common brain high recurrence rate limited treatment options, has been linked changes function. This review focuses on bioenergetics, dynamics, metastasis, autophagy mitochondria relation glioma well potential use mitochondria-targeting drugs treatment.

Language: Английский

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Targeting Metabolic and Epigenetic Vulnerabilities in Glioblastoma with SN-38 and Rabusertib Combination Therapy

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(2), P. 474 - 474

Published: Jan. 8, 2025

Glioblastoma (GBM), the most prevalent primary malignant brain tumor, remains challenging to treat due extensive inter- and intra-tumor heterogeneity. This variability demands combination treatments improve therapeutic outcomes. A significant obstacle in treating GBM is expression of O6-methylguanine-DNA methyltransferase, a DNA repair enzyme that reduces efficacy standard alkylating agent, temozolomide, about 50% patients. underscores need for novel, more targeted therapies. Our study investigates metabolic-epigenetic impact combining SN-38, novel topoisomerase inhibitor inducing double-strand breaks, with rabusertib, checkpoint kinase 1 inhibitor. We identified this synergistic through high-throughput drug screening across panel cell lines using cancer library combined SN-38. secondary metabolic PEDS algorithm demonstrated modulation purine, one-carbon, redox metabolism. Furthermore, treatment led depletion epigenetically relevant metabolites such as 5-methyl-cytosine, acetyl-lysine, trimethyl-lysine. Reduced intermediates glutathione cycle indicated increased cellular stress following combinatorial treatment. Overall, SN-38 rabusertib synergistically disrupts associated epigenetic adaptations, leading cytotoxicity independent methyltransferase status, thereby underpinning promising candidate therapy GBM.

Language: Английский

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Metabolic shifts in glioblastoma: unraveling altered pathways and exploring novel therapeutic avenues

Molecular Biology Reports, Journal Year: 2025, Volume and Issue: 52(1)

Published: Jan. 22, 2025

Language: Английский

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Targeting metabolic reprogramming in glioblastoma as a new strategy to overcome therapy resistance

Frontiers in Cell and Developmental Biology, Journal Year: 2025, Volume and Issue: 13

Published: Feb. 26, 2025

Glioblastoma (GBM) is one of the deadliest tumors due to its high aggressiveness and resistance standard therapies, resulting in a dismal prognosis. This lethal tumor carries out metabolic reprogramming order modulate specific pathways, providing metabolites that promote GBM cells proliferation limit efficacy treatments. Indeed, remodels glucose metabolism undergoes Warburg effect, fuelling glycolysis even when oxygen available. Moreover, recent evidence revealed rewiring nucleotide, lipid iron metabolism, not only an increased growth, but also radio- chemo-resistance. Thus, while on hand advantage for GBM, other it may represent exploitable target hamper progression. Lately, number studies focused drugs targeting uncover their effects therapy resistance, demonstrating some these are effective, combination with conventional treatments, sensitizing radiotherapy chemotherapy. However, heterogeneity could lead plethora alterations among subtypes, hence treatment might be effective proneural mesenchymal ones, which more aggressive resistant approaches. review explores key mechanisms involvement highlighting how acts as double-edged sword taking into account pathways seem offer promising options GBM.

Language: Английский

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From Biomarker Discovery to Clinical Applications of Metabolomics in Glioblastoma

Metabolites, Journal Year: 2025, Volume and Issue: 15(5), P. 295 - 295

Published: April 29, 2025

Background/Objectives: In recent years, interest in studying changes cancer metabolites has resulted significant advances the metabolomics field. Glioblastoma remains most aggressive and lethal brain malignancy, which presents with notable metabolic reprogramming. Methods: We performed literature research from PubMed database considered articles focused on key pathways altered glioblastoma (e.g., glycolysis, lipid metabolism, TCA cycle), role of oncometabolites plasticity, differential expression glioblastoma. Currently used approaches can be either targeted, focusing specific pathways, or untargeted, involves data-driven exploration metabolome also results identification new metabolites. Data processing analysis is great importance improved integration machine learning for metabolite identification. Results: Changes α/β-glucose, lactate, choline, 2-hydroxyglutarate were detected compared non-tumor tissues. Different such as fumarate, tyrosine, leucine, well citric acid, isocitric shikimate, GABA blood CSF, respectively. Conclusions: Although promising technological bioinformatic help us understand better, challenges associated biomarker availability, tumor heterogeneity, interpatient variability, standardization, reproducibility still remain. Metabolomics research, alone combined genomics proteomics (i.e., multiomics) glioblastoma, lead to identification, tracking therapy response, discovery novel potential therapeutic targets.

Language: Английский

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Unraveling the Role of Ubiquitin-Conjugating Enzyme UBE2T in Tumorigenesis: A Comprehensive Review

Cells, Journal Year: 2024, Volume and Issue: 14(1), P. 15 - 15

Published: Dec. 26, 2024

Ubiquitin-conjugating enzyme E2 T (UBE2T) is a crucial in the ubiquitin-proteasome system (UPS), playing significant role ubiquitination of proteins and influencing wide range cellular processes, including proliferation, differentiation, apoptosis, invasion, metabolism. Its overexpression has been implicated various malignancies, such as lung adenocarcinoma, gastric cancer, pancreatic liver ovarian where it correlates strongly with disease progression. UBE2T facilitates tumorigenesis malignant behaviors by mediating essential functions DNA repair, cell cycle regulation, activation oncogenic signaling pathways. High levels expression are associated poor survival outcomes, highlighting its potential molecular biomarker for cancer prognosis. Increasing evidence suggests that acts an oncogene could serve promising therapeutic target treatment. This review aims to provide detailed overview UBE2T’s structure, functions, mechanisms involved progression well recent developments UBE2T-targeted inhibitors. Such insights may pave way novel strategies diagnosis treatment, enhancing our understanding biology supporting development innovative approaches.

Language: Английский

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Progress in Glioma Stem Cell Research

Cancers, Journal Year: 2023, Volume and Issue: 16(1), P. 102 - 102

Published: Dec. 24, 2023

Glioblastoma multiforme (GBM) represents a diverse spectrum of primary tumors notorious for their resistance to established therapeutic modalities. Despite aggressive interventions like surgery, radiation, and chemotherapy, these tumors, due factors such as the blood–brain barrier, tumor heterogeneity, glioma stem cells (GSCs), drug efflux pumps, DNA damage repair mechanisms, persist beyond complete isolation, resulting in dismal outcomes patients. Presently, standard initial approach comprises surgical excision followed by concurrent where temozolomide (TMZ) serves foremost option managing GBM Subsequent adjuvant chemotherapy follows this regimen. Emerging approaches encompass immunotherapy, including checkpoint inhibitors, targeted treatments, bevacizumab, aiming exploit vulnerabilities within cells. Nevertheless, there exists pressing imperative devise innovative strategies both diagnosing treating GBM. This review emphasizes current knowledge GSC biology, molecular associations with various signals and/or pathways, epidermal growth factor receptor, PI3K/AKT/mTOR, HGFR/c-MET, NF-κB, Wnt, Notch, STAT3 pathways. Metabolic reprogramming GSCs has also been reported prominent activation glycolytic pathway, comprising aldehyde dehydrogenase family genes. We discuss potential targets currently used well mode action on targets.

Language: Английский

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ALOX5 contributes to glioma progression by promoting 5-HETE-mediated immunosuppressive M2 polarization and PD-L1 expression of glioma-associated microglia/macrophages

Journal for ImmunoTherapy of Cancer, Journal Year: 2024, Volume and Issue: 12(8), P. e009492 - e009492

Published: Aug. 1, 2024

Oxylipin metabolism plays an essential role in glioma progression and immune modulation the tumor microenvironment. Lipid metabolic reprogramming has been linked to macrophage remodeling, while understanding of oxylipins their catalyzed enzymes lipoxygenases regulation glioma-associated microglia/macrophages (GAMs) remains largely unexplored.

Language: Английский

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Radiosensitizing Capacity of Fenofibrate in Glioblastoma Cells Depends on Lipid Metabolism

Redox Biology, Journal Year: 2024, Volume and Issue: 79, P. 103452 - 103452

Published: Dec. 3, 2024

Despite advances in multimodal therapy approaches such as resection, chemotherapy and radiotherapy, the overall survival of patients with grade 4 glioblastoma (GBM) remains extremely poor (average time <2 years). Altered lipid metabolism, which increases fatty acid synthesis thereby contributes to radioresistance GBM, is a hallmark cancer. Therefore, we explored radiosensitizing effect clinically approved, lipid-lowering drug fenofibrate (FF) different GBM cell lines (U87, LN18). Interestingly, FF (50 μM) significantly radiosensitizes U87 cells by inducing DNA double-strand breaks through oxidative stress impairing mitochondrial membrane integrity, but radioprotects LN18 reducing production reactive oxygen species (ROS) stabilizing potential. A comparative protein analysis revealed striking differences two lines: exhibited higher expression density (FA) cluster transporter CD36 than cells, glycerol-3-phosphate acyltransferase (GPAT4) supports large droplets (LDs), lower diacylglycerol O-acyltransferase 1 (DGAT1) regulates formation small LDs. Consequently, LDs are predominantly found whereas cells. After combined treatment irradiation, number increased radioresistant decreased radiosensitive The radioprotective could be associated presence LDs, act sink for lipophilic FF. To prevent uptake ameliorate its function radiosensitizer, was encapsulated biomimetic extracellular vesicles (CmEVs) alter intracellular trafficking drug. In contrast free drug, CmEV-encapsulated enriched lysosomal compartment, causing necrosis integrity. Since stability plasma membranes maintained stress-inducible heat shock 70 (Hsp70) has strong affinity tumor-specific glycosphingolipids, occurs having Hsp70 summary, our findings indicate that metabolism tumor can affect capacity when encountered either or loaded vesicles.

Language: Английский

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BCL2L13 Influences Autophagy and Ceramide Metabolism without Affecting Temozolomide Resistance in Glioblastoma

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 26, 2024

Abstract Temozolomide (TMZ) resistance in glioblastoma (GB) poses a significant therapeutic challenge. We developed TMZ-resistant (TMZ-R) U251 GB model, revealing distinct differences cell viability, apoptosis, autophagy, and lipid metabolism between TMZ-R non-resistant (TMZ-NR) cells. TMZ-NR cells exhibited heightened sensitivity to TMZ-induced while cells-maintained viability. Autophagy flux was completely inhibited cells, indicated by LC3βII SQSTM1 accumulation. BCL2L13, which showed higher expression demonstrated increased interaction with Ceramide Synthase 6 (CerS6) reduced 2 (CerS2) BCL2L13 knockdown (KD) disrupted autophagy flux, decreasing autophagosome accumulation increasing it These changes contributed altered ceramide profiles, where displayed elevated levels of Cer 16:0, 18:0, 20:0, 22:0, 24:0, 24:1. Our findings highlight as potential targets overcome TMZ GB.

Language: Английский

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