O-GlcNAcylation in cancer development and immunotherapy

Cancer Letters, Journal Year: 2023, Volume and Issue: 566, P. 216258 - 216258

Published: June 4, 2023

Language: Английский

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Itaconate transporter SLC13A3 confers immunotherapy resistance via alkylation-mediated stabilization of PD-L1

Cell Metabolism, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Itaconate is a metabolite catalyzed by cis-aconitate decarboxylase (ACOD1), which mainly produced activated macrophages and secreted into the extracellular environment to exert complex bioactivity. In tumor microenvironment, itaconate concentrated induces an immunosuppressive response. However, whether can be taken up cells its mechanism of action remain largely unclear. Here, we identified solute carrier family 13 member 3 (SLC13A3) as key protein transporting cells, where it elevates programmed cell death ligand 1 (PD-L1) levels decreases expression immunostimulatory molecules, thereby promoting immune evasion. Mechanistically, alkylates cysteine 272 residue on PD-L1, antagonizing PD-L1 ubiquitination degradation. Consequently, SLC13A3 inhibition enhances efficacy anti-CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) immunotherapy improves overall survival rate in syngeneic mouse models. Collectively, our findings transporter revealed immunomodulatory role, providing combinatorial strategies overcome resistance tumors.

Language: Английский

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Therapy-induced senescent cancer cells contribute to cancer progression by promoting ribophorin 1-dependent PD-L1 upregulation

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 3, 2025

Language: Английский

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Sonodynamic Activated Nanoparticles with Glut1 Inhibitor and Cystine-containing Polymer Stimulate Disulfidptosis for Improved Immunotherapy in Bladder Cancer

Biomaterials, Journal Year: 2025, Volume and Issue: 319, P. 123178 - 123178

Published: Feb. 8, 2025

Language: Английский

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On a sugar high: Role of O-GlcNAcylation in cancer

Journal of Biological Chemistry, Journal Year: 2023, Volume and Issue: 299(11), P. 105344 - 105344

Published: Oct. 12, 2023

Recent advances in the understanding of molecular mechanisms underlying cancer progression have led to development novel therapeutic targeting strategies. Aberrant glycosylation patterns and their implication gained increasing attention as potential targets due critical role regulating tumor-specific pathways that contribute cell survival, proliferation, progression. A special type has been gaining momentum research is modification nuclear, cytoplasmic, mitochondrial proteins, termed O-GlcNAcylation. This protein catalyzed by an enzyme called O-GlcNAc transferase (OGT), which uses final product Hexosamine Biosynthetic Pathway (HBP) connect altered nutrient availability changes cellular signaling multiple aspects tumor Both its OGT are highly elevated fulfill crucial many hallmarks cancer. In this review, we present discuss latest findings elucidating involvement

Language: Английский

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Emerging roles of O-GlcNAcylation in protein trafficking and secretion

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: 300(3), P. 105677 - 105677

Published: Jan. 23, 2024

The emerging roles of O-GlcNAcylation, a distinctive post-translational modification, are increasingly recognized for their involvement in the intricate processes protein trafficking and secretion. This modification exerts its influence on both conventional unconventional secretory pathways. Under healthy stress conditions, such as during diseases, it orchestrates transport proteins within cells, ensuring timely delivery to intended destinations. O-GlcNAcylation occurs key factors, like coat complexes (COPI COPII), clathrin, SNAREs (soluble N-ethylmaleimide-sensitive factor attachment receptors), GRASP55 (Golgi reassembly stacking 55 kDa) that control vesicle budding fusion anterograde retrograde understanding offers valuable insights into critical functions cellular physiology progression including neurodegeneration, cancer, metabolic disorders. In this review, we summarize discuss latest findings elucidating O-GlcNAc significance various human

Language: Английский

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Targeting O-GlcNAcylation in cancer therapeutic resistance: The sugar Saga continues

Cancer Letters, Journal Year: 2024, Volume and Issue: 588, P. 216742 - 216742

Published: Feb. 23, 2024

Language: Английский

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Altered glycosylation in cancer: molecular functions and therapeutic potential

Cancer Communications, Journal Year: 2024, Volume and Issue: 44(11), P. 1316 - 1336

Published: Sept. 21, 2024

Abstract Glycosylation, a key mode of protein modification in living organisms, is critical regulating various biological functions by influencing folding, transportation, and localization. Changes glycosylation patterns are significant feature cancer, associated with range pathological activities cancer‐related processes, serve as biomarkers providing new targets for cancer diagnosis treatment. Glycoproteins like human epidermal growth factor receptor 2 (HER2) breast alpha‐fetoprotein (AFP) liver carcinoembryonic antigen (CEA) colon prostate‐specific (PSA) prostate all tumor approved clinical use. Here, we introduce the diversity structures newly discovered substrate—glycosylated RNA (glycoRNA). This article focuses primarily on metastasis, immune evasion, metabolic reprogramming, aberrant ferroptosis responses, cellular senescence to illustrate role cancer. Additionally, summarize applications diagnostics, treatment, multidrug resistance. We envision promising future glycosylation.

Language: Английский

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Proximity Labeling-Based Identification of MGAT3 Substrates and Revelation of the Tumor-Suppressive Role of Bisecting GlcNAc in Breast Cancer via GLA Degradation

Cells, Journal Year: 2025, Volume and Issue: 14(2), P. 103 - 103

Published: Jan. 12, 2025

Glycosylation plays a critical role in various biological processes, yet identifying specific glycosyltransferase substrates remains challenge due to the complexity of glycosylation. Here, we employ proximity labeling with biotin ligases BASU and TurboID map proximitome MGAT3, responsible for biosynthesis bisecting GlcNAc structure, HEK293T cells. This approach enriched 116 189 proteins, respectively, 17 common shared GlcNAc-bearing proteome obtained via intact glycopeptide enrichment methods. Gene ontology analysis revealed that proteins were predominantly localized exosome, endoplasmic reticulum, Golgi apparatus, consistent subcellular localization MGAT3 substrates. Notably, four novel substrates, GOLM2, CCDC134, ASPH, ERO1A, confirmed bear modification, validating utility method. Furthermore, observed modification inhibits breast cancer progression by promoting degradation α-galactosidase A (GLA). These findings demonstrate efficacy provide insights into functional impact modification.

Language: Английский

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O-GlcNAcylation of MITF regulates its activity and CDK4/6 inhibitor resistance in breast cancer

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: July 3, 2024

Abstract Cyclin-dependent kinases 4 and 6 (CDK4/6) play a pivotal role in cell cycle cancer development. Targeting CDK4/6 has demonstrated promising effects against breast cancer. However, resistance to inhibitors (CDK4/6i), such as palbociclib, remains substantial challenge clinical settings. Using high-throughput combinatorial drug screening genomic sequencing, we find that the microphthalmia-associated transcription factor (MITF) is activated via O-GlcNAcylation by O-GlcNAc transferase (OGT) palbociclib-resistant cells tumors. Mechanistically, of MITF at Serine 49 enhances its interaction with importin α/β, thus promoting translocation nuclei, where it suppresses palbociclib-induced senescence. Inhibition or re-sensitizes resistant palbociclib. Moreover, studies confirm activation tumors from patients who are undergoing palbociclib treatment. Collectively, our shed light on mechanism regulating present evidence for developing therapeutic approaches treat CDK4/6i-resistant patients.

Language: Английский

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