Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 147, P. 107400 - 107400
Published: April 25, 2024
Language: Английский
Advanced Science, Journal Year: 2024, Volume and Issue: 11(18)
Published: March 9, 2024
Abstract Gastric cancer (GC) presents a formidable global health challenge, and conventional therapies face efficacy limitations. Ubiquitin‐specific protease 7 (USP7) plays pivotal roles in GC development, immune response, chemo‐resistance, making it promising target. Various USP7 inhibitors have shown selectivity preclinical studies. However, the mechanistic role of has not been fully elucidated, currently, no approved for clinical use. In this study, DHPO is identified as potent inhibitor treatment through silico screening. demonstrates significant anti‐tumor activity vitro, inhibiting cell viability clonogenic ability, preventing tumor migration invasion. vivo studies using orthotopic gastric mouse models validate DHPO's suppressing growth metastasis without toxicity. Mechanistically, inhibition triggers ferroptosis, evidenced by mitochondrial alterations, lipid Reactive Oxygen Species (ROS), Malondialdehyde (MDA) accumulation, iron overload. Further investigations unveil USP7's regulation Stearoyl‐CoA Desaturase (SCD) deubiquitination, linking to SCD degradation ferroptosis induction. Overall, study identifies key player GC, elucidates inhibitory mechanisms, highlights its potential inducing regulation.
Language: Английский
Citations
19
Cellular & Molecular Biology Letters, Journal Year: 2025, Volume and Issue: 30(1)
Published: Jan. 6, 2025
Abstract Hypoxia-inducible factors (HIFs) are essential transcription that orchestrate cellular responses to oxygen deprivation. HIF-1α, as an unstable subunit of HIF-1, is usually hydroxylated by prolyl hydroxylase domain enzymes under normoxic conditions, leading ubiquitination and proteasomal degradation, thereby keeping low levels. Instead hypoxia, sometimes even in normoxia, HIF-1α translocates into the nucleus, dimerizes with HIF-1β generate then activates genes involved adaptive such angiogenesis, metabolic reprogramming, survival, which presents new challenges insights its role processes. Thus, review delves mechanisms HIF-1 maintains stability normoxia including but not limited giving transcriptional, translational, well posttranslational regulation underscore pivotal adaptation malignancy. Moreover, extensively cancer cardiovascular diseases potentially serves a bridge between them. An overview HIF-1-related drugs approved or clinical trials summarized, highlighting their potential capacity for targeting toxicity related treatment. The provides comprehensive insight HIF-1’s regulatory mechanism paves way future research therapeutic development.
Language: Английский
Citations
6
European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 117324 - 117324
Published: Jan. 1, 2025
Language: Английский
Citations
4
Journal of Experimental & Clinical Cancer Research, Journal Year: 2025, Volume and Issue: 44(1)
Published: Jan. 25, 2025
Abstract Background Exosomes, as extracellular membrane vesicles, play important roles in intercellular communication and can influence tumour progression. Circular RNAs (circRNAs) have been reported various malignancies are also components of exosomes. However, the role exosomal circRNAs gastric cancer (GC) progression has not completely clarified. Methods The enriched GC were identified using circRNA sequencing. biological function circMAN1A2 was investigated a series vitro vivo experiments. PKH-67 staining used to label molecular mechanism via mass spectrometry, immunoprecipitation, Western blot, single-cell RNA-sequencing data analyses. Results In our study, we determined that (hsa_circ_0000118) GC-derived Higher expression related poor survival patients (HR = 2.917, p 0.0120). Exosomal promoted suppressed antitumour activity T cells. Moreover, bound SFPQ cells cells, promoting G1/S phase transition cell cycle while inhibiting activation receptor signalling pathway decrease activity. Mechanistically, competed with FBXW11 for binding SFPQ, preventing FBXW11-mediated k48-linked ubiquitination protein degradation, thereby stabilizing expression. Conclusions Our work confirms critical immunosuppression GC. This novel axis circMAN1A2-SFPQ provides new insights into circRNA-based diagnostic therapeutic strategies.
Language: Английский
Citations
3
Redox Biology, Journal Year: 2024, Volume and Issue: 75, P. 103259 - 103259
Published: June 27, 2024
Ferroptosis is a form of iron-related oxidative cell death governed by an integrated redox system, encompassing pro-oxidative proteins and antioxidative proteins. These undergo precise control through diverse post-translational modifications, including ubiquitination, phosphorylation, acetylation, O-GlcNAcylation, SUMOylation, methylation, N-myristoylation, palmitoylation, modification. modifications play pivotal roles in regulating protein stability, activity, localization, interactions, ultimately influencing both the buildup iron lipid peroxidation. In mammalian cells, regulators ferroptosis typically degradation via two principal pathways: ubiquitin-proteasome which handles majority degradation, autophagy, primarily targeting long-lived or aggregated This comprehensive review aims to summarize recent advances modification linked ferroptosis. It also discusses strategies for modulating systems, providing new insights into potential therapeutic applications cancer non-neoplastic diseases.
Language: Английский
Citations
16
Journal of Experimental & Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 43(1)
Published: Feb. 2, 2024
Abstract Background Ubiquitination plays an important role in proliferating and invasive characteristic of glioblastoma (GBM), similar to many other cancers. Tripartite motif 25 (TRIM25) is a member the TRIM family proteins, which are involved tumorigenesis through substrate ubiquitination. Methods Difference TRIM25 expression levels between nonneoplastic brain tissue samples primary glioma was demonstrated using publicly available database, immunohistochemistry, western blotting. knockdown GBM cell lines (LN229 U251) patient derived stem-like cells (GSCs) GBM#021 were used investigate function vivo vitro. Co-immunoprecipitation (Co-IP) mass spectrometry analysis performed identify NONO as protein that interacts with TRIM25. The molecular mechanisms underlying promotion development by investigated RNA-seq validated qRT-PCR Results We observed upregulation GBM, correlating enhanced growth invasion, both vitro vivo. Subsequently, we screened panel proteins interacting TRIM25; co-immunoprecipitation revealed potential reduced K63-linked ubiquitination NONO, thereby suppressing splicing NONO. Dysfunctional resulted retention second intron pre-mRNA PRMT1, inhibiting activation PRMT1/c-MYC pathway. Conclusions Our study demonstrates promotes invasion regulating pathway mediation factor Targeting E3 ligase activity or complex interactions may prove beneficial treatment GBM.
Language: Английский
Citations
12
Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)
Published: Sept. 19, 2024
Language: Английский
Citations
10
Theranostics, Journal Year: 2025, Volume and Issue: 15(6), P. 2428 - 2450
Published: Jan. 20, 2025
Rationale: Abnormal metabolic states contribute to a variety of diseases, including cancer. RNA modifications have diverse biological functions and are implicated in cancer development, gastric (GC). However, the direct relationship between glucose homeostasis 4-acetylcytosine (ac4C) modification GC remains unclear. Methods: The prognostic value acetyltransferase NAT10 expression was evaluated human cohort. Additionally, preoperative PET/CT data from patients Micro-PET/CT imaging mice were employed assess metabolism. role investigated through various experiments, xenografts, organoids, conditional knockout (cKO) mouse model. underlying mechanisms examined using dot blotting, immunofluorescence staining, co-immunoprecipitation, high-throughput sequencing, among other techniques. Results: Glucose deprivation activates autophagy-lysosome pathway, leading degradation by enhancing its interaction with sequestosome 1 (SQSTM1)/microtubule-associated protein light chain 3 alpha (LC3) complex, ultimately resulting reduction ac4C modification. Furthermore, levels elevated tissues correlate poor prognosis. A strong correlation exists 18F-FDG uptake patients. drives glycolytic metabolism carcinogenesis vitro vivo. Mechanistically, stimulates at intersection coding sequence (CDS) 3' untranslated region (3'UTR) hexokinase 2 (HK2) mRNA, stability activating thereby driving tumorigenesis. Conclusion: Our findings highlight critical crosstalk epitranscriptome carcinogenesis. This finding offers potential strategy targeting NAT10/HK2 axis for treatment patients, especially those highly active
Language: Английский
Citations
2
Clinical & Translational Oncology, Journal Year: 2025, Volume and Issue: unknown
Published: Feb. 10, 2025
Language: Английский
Citations
2
Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: 21(3)
Published: March 1, 2025
Abstract In Alzheimer's disease (AD), tau undergoes abnormal post‐translational modifications and aggregations. Impaired intracellular degradation pathways further exacerbate the accumulation of pathological tau. A new strategy – targeted protein recently emerged as a modality in drug discovery where bifunctional molecules bring target close to machinery promote clearance. Since 2016, this has been applied pathologies attracted broad interest academia pharmaceutical industry. However, systematic review recent studies on mechanisms is lacking. Here we (the ubiquitin–proteasome system autophagy–lysosome pathway), their dysfunction AD, tau‐targeted degraders, such proteolysis‐targeting chimeras autophagy‐targeting chimeras. We emphasize need for continuous exploration provide future perspective developing encouraging researchers work treatment options AD patients. Highlights Post‐translational modifications, aggregation, mutations affect degradation. vicious circle exists between impaired pathologies. Ubiquitin plays an important role complex pathways. Tau‐targeted degraders promising strategies novel treatment.
Language: Английский
Citations
2