The cGAS–STING, p38 MAPK, and p53 pathways link genome instability to accelerated cellular senescence in ATM-deficient murine lung fibroblasts

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(2)

Published: Jan. 7, 2025

Ataxia–telangiectasia (A-T) is a pleiotropic genome instability syndrome resulting from the loss of homeostatic protein kinase ATM. The complex phenotype A-T includes progressive cerebellar degeneration, immunodeficiency, gonadal atrophy, interstitial lung disease, cancer predisposition, endocrine abnormalities, chromosomal instability, radiosensitivity, and segmental premature aging. Cultured skin fibroblasts patients exhibit senescence, highlighting association between cellular We found that derived ATM-deficient mice provide versatile experimental system to explore mechanisms driving senescence primary lacking Atm −/− failed proliferate under ambient oxygen conditions (21%). Although they initially proliferated physiological levels (3%), rapidly entered senescence. In contrast, wild-type (WT) did not senesce 3% eventually underwent immortalization neoplastic transformation. However, rapid could be induced in WT cells either by gene ablation or persistent chemical inhibition ATM activity, with being reversible upon inhibitor removal. Moreover, concomitant p53 led evasion, vigorous growth, rampant subsequent Our findings reveal driven collaborative action cGAS–STING, p38 MAPK, pathways response DNA damage, ultimately leading induction interferon-α1 downstream interferon-stimulated genes. propose accelerated may exacerbate specific symptoms, particularly contributing progressive, life-threatening disease often observed during adulthood.

Language: Английский

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Dual inhibitors of DNMT and HDAC remodels the immune microenvironment of colorectal cancer and enhances the efficacy of anti-PD-L1 therapy

Pharmacological Research, Journal Year: 2024, Volume and Issue: 206, P. 107271 - 107271

Published: June 19, 2024

Colorectal cancer is the second most prevalent and deadly worldwide. The emergence of immune checkpoint therapy has provided a revolutionary strategy for treatment solid tumors. However, less than 5 % colorectal patients respond to therapy. Thus, it great scientific significance develop "potentiators" In this study, we found that knocking down different DNMT HDAC isoforms could increase expression IFNs in cells, which can enhance effectiveness Therefore, combined inhibition cloud synergistically effect immunotherapy. We dual inhibitors C02S inhibit tumor growth immunocompetent mice but not immunocompromised nude mice, indicates exerts its antitumor effects through system. Mechanistically, ERVs, generated intracellular levels dsRNA then promotes RIG-I/MDA5-MAVS signaling pathway. Moreover, increased infiltration DCs T cells microenvironment, enhanced efficacy anti-PD-L1 MC38 CT26 model. These results confirmed activate pathway, remodel microenvironment therapy, provides new evidence solutions development "potentiator"

Language: Английский

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Differential Response to Local Stimulator of Interferon Genes Agonist Administration in Tumors with Various Stimulator of Interferon Genes Statuses

Cancers, Journal Year: 2025, Volume and Issue: 17(2), P. 175 - 175

Published: Jan. 8, 2025

Background/Objectives: The stimulator of interferon genes (STING) is currently accepted as a relevant target for anti-cancer therapies. Besides encouraging results showing STING agonist-induced tumor growth inhibition, in some types tumors the effect less prominent. We hypothesized that higher levels cancer cells and possibility its activation determine greater response. As local administration agonists induces systemic reaction, we emphasized importance host tumor-induced hematological disruption efficiency therapeutic Methods: investigated response to stimulation murine cell lines-melanoma (B16-F10) breast carcinoma (4T1)-and normal lines: fibroblast (NIH/3T3), endothelial (H5V), macrophages (J774A.1). assessed inhibition therapy's impact on system parameters cytokine release. Results: Our underlined improved melanoma over (4T1) tumors. outcomes reflected high dysregulation mice with developed 4T1 tumors, which may support persistent inflammation impede STING-induced effects. Moreover, among typical cytokines produced following activation, CCL2 fold change was one increased most serum B16-F10-bearing differentiated observed agonist between models. Conclusions: current study provides new evidence different responses two poorly immunogenic abundance B16-F10 linked vivo compared 4T1. also seems be connected dysregulated This highlighted need general insight into proposed therapy.

Language: Английский

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cGAS-STING: mechanisms and therapeutic opportunities

Science China Life Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 14, 2025

Language: Английский

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Ginsenoside RG3 Synergizes With STING Agonist to Reverse Cisplatin Resistance in Gastric Cancer

Food Science & Nutrition, Journal Year: 2025, Volume and Issue: 13(1)

Published: Jan. 1, 2025

ABSTRACT This study investigates the synergistic inhibitory effects of combining stimulator interferon genes (STING) agonist cyclic diadenylate monophosphate (c‐di‐AMP) and ginsenoside RG3 on cisplatin (DDP)‐resistant gastric cancer (GC) cells. The objective is to identify novel therapeutic targets offers insights for clinical management DDP resistance. Various techniques were employed, including western blot, MTT assay, colony formation scratch transwell tubule flow cytometry, Hoechst 33342 fluorescence staining, in vivo experiments, investigate potential mechanisms combined application STING reversing resistance cancer. combination markedly suppressed key malignant behaviors, proliferation, migration, invasion, angiogenesis SGC‐7901/DDP Additionally, this treatment inhibited epithelial‐mesenchymal transition (EMT) process stem cell‐like characteristics cells, while downregulating expression resistance‐related proteins. effectively suppresses growth proliferation Ginsenoside RG3, well‐documented its multifaceted properties, antioxidant, anti‐aging, anti‐cancer effects, widely used managing chemotherapy‐related side effects. Furthermore, enhances anti‐tumor immunity by regulating signal transduction. comprehensively evaluated efficacy through vitro demonstrating significant inhibition progression reversal drug These findings offer a robust theoretical foundation applications highlight new future research.

Language: Английский

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MicroRNAs in the Mitochondria–Telomere Axis: Novel Insights into Cancer Development and Potential Therapeutic Targets

Genes, Journal Year: 2025, Volume and Issue: 16(3), P. 268 - 268

Published: Feb. 25, 2025

The mitochondria–telomere axis is recognized as an important factor in the processes of metabolism, aging and oncogenesis. MicroRNAs (miRNAs) play essential function this complex interaction, having impact on aspects such cellular homeostasis, oxidative responses apoptosis. In recent years, miRNAs have been found to be crucial for telomeric stability, well mitochondrial behavior, factors that influence cell proliferation viability. Furthermore, (mitomiRs) are associated with gene expression activity cGAS/STING pathway activity, linking DNA recognition immune system responses. Hence, maintain a link biogenesis, metabolic changes cancer organelles. This review focuses roles variety progression their potential application biomarkers or therapeutic agents.

Language: Английский

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STING immune activation of microglia aggravating neurovascular unit damage in diabetic retinopathy

Free Radical Biology and Medicine, Journal Year: 2025, Volume and Issue: 233, P. 86 - 101

Published: March 30, 2025

Language: Английский

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Digitoflavone Ameliorates Acute Lung Injury via Disturbing the Formation of Functional Stimulator of Interferon Genes Signalosome

World Journal of Traditional Chinese Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: April 17, 2025

Abstract Objective: The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon (IFN) genes (STING) signaling pathway has been implicated in the initiation and maintenance a variety inflammatory diseases. Thus, search for modulators cGAS-STING is likely to contribute their therapeutic prevention treatment. Natural products from traditional Chinese medicine are an important source modern drug development; digitoflavone (DG), natural flavonoid present plants, shown have anti-inflammatory effects. However, its specific mechanisms action remain unclear yet be used clinical settings. Materials Methods: activation was modeled bone marrow-derived macrophages (BMDMs) human leukemia monocytic cell line (THP-1) cells vivo , expression type I IFN-related pro-inflammatory cytokines detected after DG pretreatment. Next, we examined effect on STING downstream events, such as oligomerization functional signalosome formation. Using experiments, 5,6-dimethylxanthenone-4-acetic acid (DMXAA)-induced agonist lipopolysaccharide-induced acute lung injury models were assay effects DG. Results: effectively inhibited pathway, which accompanied by increase levels IFN BMDMs THP-1 cells. did not affect but STING-Interferon Regulatory Factor 3 (IRF3) or TANK-binding kinase 1-IRF3 binding. In addition, induced DMXAA while demonstrating favorable injury. Conclusions: Our results suggest that inhibitor may act affecting formation pathways. Moreover, ameliorative could treat pathway-mediated

Language: Английский

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The cGAS-STING pathway drives neuroinflammation and neurodegeneration via cellular and molecular mechanisms in neurodegenerative diseases

Neurobiology of Disease, Journal Year: 2024, Volume and Issue: 202, P. 106710 - 106710

Published: Oct. 28, 2024

Neurodegenerative diseases (NDs) are a type of common chronic progressive disorders characterized by damage to specific cell populations in the nervous system, ultimately leading disability or death. Effective treatments for these still lacking, due limited understanding their pathogeneses, which involve multiple cellular and molecular pathways. The triggering an immune response is feature neurodegenerative disorders. A critical challenge intricate interplay between neuroinflammation, neurodegeneration, responses, not yet fully characterized. In recent years, cyclic GMP-AMP synthase (cGAS)-stimulator interferon gene (STING) pathway, crucial intracellular DNA sensing, has gradually gained attention. However, roles this pathway within types such as cells, glial neuronal its contribution ND pathogenesis, remain elucidated. review, we systematically explore how cGAS-STING signaling links various with related effector pathways under context NDs multifaceted therapeutic directions. We emphasize discovery condition-dependent heterogeneity integral diverse responses potential targets. Additionally, review pathogenic role activation Parkinson's disease, ataxia-telangiectasia, amyotrophic lateral sclerosis. focus on complex bidirectional Alzheimer's Huntington's sclerosis, revealing double-edged nature disease progression. objective elucidate pivotal pathogenesis catalyze new insights facilitating development novel strategies.

Language: Английский

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Ultrarare Variants in DNA Damage Repair Genes in Pediatric Acute-Onset Neuropsychiatric Syndrome or Acute Behavioral Regression in Neurodevelopmental Disorders

Developmental Neuroscience, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 20

Published: Oct. 11, 2024

Introduction: Acute onset of severe psychiatric symptoms or regression may occur in children with premorbid neurodevelopmental disorders, although typically developing can also be affected. Infections other stressors are likely triggers. The underlying causes unclear, but a current hypothesis suggests the convergence genes that influence neuronal and immunological function. We previously identified 11 pediatric acute-onset neuropsychiatric syndrome (PANS), which two classes related to either synaptic function immune system were found. Among latter, three affect DNA damage response (DDR): PPM1D, CHK2, RAG1. now report an additional 17 cases mutations PPM1D DDR patients acute and/or their clinicians classified as PANS another inflammatory brain condition. Methods: analyzed genetic findings obtained from parents carried out whole-exome sequencing on total cases, included 3 sibling pairs family 4 affected children. Results: include clusters affecting p53 repair (PPM1D, ATM, ATR, 53BP1, RMRP), Fanconi Anemia Complex (FANCE, SLX4/FANCP, FANCA, FANCI, FANCC). hypothesize defects genes, context infection stressors, could contribute decompensated states through increase genomic instability concomitant accumulation cytosolic cells triggering sensors, such cGAS-STING AIM2 inflammasomes, well central deficits neuroplasticity. In addition, increased senescence defective apoptosis responses playing role. Conclusion: These compelling preliminary motivate further functional characterization downstream impact point novel treatment strategies.

Language: Английский

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