Disruption of GPSM1/CSF1 signaling reprograms tumor-associated macrophages to overcome anti-PD-1 resistance in colorectal cancer

Journal for ImmunoTherapy of Cancer, Journal Year: 2025, Volume and Issue: 13(2), P. e010826 - e010826

Published: Feb. 1, 2025

Background Immune checkpoint blockade (ICB) therapies, particularly anti-PD-1, benefit only a limited subset of colorectal cancer (CRC) patients. G-protein signaling modulator 1 (GPSM1) is implicated in immunity and oncology, yet its role regulating the CRC tumor microenvironment (TME) contributing to anti-PD-1 resistance remains poorly understood. Methods We employed single-cell RNA sequencing multiplex immunofluorescence on samples from anti-PD-1-resistant patients evaluate GPSM1 expression impact macrophage polarization. An orthotopic xenograft model C57BL/6 mice was used assess vivo. vitro co-culture system, alongside mass cytometry flow cytometry, explored GPSM1’s biological functions within TME. further ChIP-PCR, spectrometry, co-immunoprecipitation elucidate mechanisms activity. Results significantly elevated tissues. Enhanced levels promoted by driving polarization toward an immunosuppressive M2 phenotype, facilitating their infiltration into identified deubiquitinase USP9X as key factor preventing degradation through K63-polyubiquitination. This stabilization led MEIS3 nuclear translocation, activating colony-stimulating expression. Importantly, ruxolitinib emerged promising GPSM1-targeting candidate, demonstrating improved efficacy combination with therapy both microsatellite instability-high stable models. Conclusions Our findings highlight pivotal GPSM1-driven mediating CRC. Targeting offers novel therapeutic strategy enhance ICB efficacy, potentially broadening patient population that may these therapies.

Language: Английский

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Proteasomal Dysfunction in Cancer: Mechanistic Pathways and Targeted Therapies

Journal of Cellular Biochemistry, Journal Year: 2025, Volume and Issue: 126(1)

Published: Jan. 1, 2025

ABSTRACT Proteasomes are the catalytic complexes in eukaryotic cells that decide fate of proteins involved various cellular processes an energy‐dependent manner. The proteasomal system performs its function by selectively destroying labelled with small protein ubiquitin. Dysfunctional activity is allegedly clinical disorders such as cancer, neurodegenerative disorders, ageing, and so forth, making it important therapeutic target. Notably, compared to healthy cells, cancer have a higher homeostasis requirement faster turnover rate. ubiquitin‐proteasome (UPS) helps increase rapidly experience less apoptotic cell death. Therefore, understanding UPS essential design discover some effective inhibitors for therapy. Hereby, we focused on role 26S proteasome complex, mainly UPS, carcinogenesis seeking potential targets treating numerous cancers.

Language: Английский

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Development of a nano-targeting chimera for the degradation of membrane and cytoplasmic proteins

Acta Biomaterialia, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

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Inhibition of CDC27 O-GlcNAcylation coordinates the antitumor efficacy in multiple myeloma through the autophagy-lysosome pathway

Acta Pharmacologica Sinica, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 21, 2025

Abstract Multiple myeloma (MM) is a prevalent hematologic malignancy characterized by abnormal proliferation of cloned plasma cells. Given the aggressive nature and drug resistance MM cells, identification novel genes could provide valuable insights for treatment. In this study we performed machine learning in RNA microarray data purified cell samples from five independent cohorts with 957 patients, identified O-GlcNAcylation transferase ( OGT ) division cycle 27 CDC27 as key prognostic MM. We demonstrated close link between cells knockdown siOGT, pharmacological inhibition OSMI-1 accumulation Thiamet G. Using mass spectrometry immunoprecipitation, O-GlcNAcylated protein target that may be directly downregulated MM.1S further revealed maintained stability blocking autophagy-lysosome pathway (ALP). Moreover, enhanced antitumor efficacy combined bortezomib (BTZ) treatment both vivo vitro. Thus, identifies function O-GlcNAcylation-related ALP regulating potential therapeutic strategy treating

Language: Английский

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Hematopoietic stem cell conditioned media induces apoptosis in colorectal cancer stem cells via dysregulation of HSP90 and 26S proteasome system

The International Journal of Biochemistry & Cell Biology, Journal Year: 2025, Volume and Issue: unknown, P. 106773 - 106773

Published: April 1, 2025

Language: Английский

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Harnessing lysosomal genetics: development of a risk stratification panel and unveiling of DPP7 as a biomarker for colon adenocarcinoma

Journal of genetics and genomics/Journal of Genetics and Genomics, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Lysosomal dysfunction has been implicated in the progression of colon adenocarcinoma (COAD), yet prognostic significance and therapeutic potential lysosome-related genes (LRGs) remain underexplored. In this study, we construct a 6-LRG-based risk stratification model (DPP7, ADAM8, CD1B, LRP2, ATP6V1C2, PLAAT3) by integrating LASSO Cox regression analyses. Stratifying patients based on median scores, demonstrate that high-risk exhibit significantly worse clinical outcomes across TCGA cohort five independent GEO datasets. Furthermore, panel outperforms 136 previously published models terms predictive accuracy for 1-, 3-, 5-year survival rates. Validation multiplex immunofluorescence using an in-house tissue microarray confirms 6-LRG signature serves as factor. Additionally, distinct immunosuppressive tumor microenvironment aggressive malignancy characteristics. Functional depletion DPP7 inhibits cell proliferation, migration, metastasis both vitro vivo settings. Moreover, silencing attenuates epithelial-mesenchymal transition, evidenced upregulation E-cadherin downregulation N-cadherin, Vimentin, Snail. conclusion, study establishes LRG-based COAD prediction nominates promising target treatment.

Language: Английский

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Regulation of PEST-containing nuclear proteins in cancer cells: implications for cancer biology and therapy

Frontiers in Oncology, Journal Year: 2025, Volume and Issue: 15

Published: April 22, 2025

The PEST-containing nuclear protein (PCNP) is a involved in the regulation of cell cycle progression, degradation, and tumorigenesis. PCNP contains PEST sequence, polypeptide structural motif rich proline (P), glutamic acid (E), serine (S), threonine (T), which serves as proteolytic recognition signal. degradation specific proteins via sequence plays crucial role modulating signaling pathways that control growth, differentiation, apoptosis, stress responses. primarily degraded through ubiquitin-proteasome system (UPS) calpain pathway, with phosphorylation residues further accelerating its degradation. ubiquitination by ring finger NIRF an E3 ligase-dependent manner well documented, along involvement MAPK PI3K/AKT/mTOR pathways. Additionally, implicated p53-mediated arrest are essential for inhibiting tumor growth. To explore cancer, this review examines effects on proliferation, apoptosis lung adenocarcinoma, thyroid ovarian other malignancies derived from glandular epithelial cells. By focusing regulatory mechanisms, study provides scientific basis research biological functions development cancer progression.

Language: Английский

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Antioxidant Role of Probiotics in Inflammation-Induced Colorectal Cancer

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(16), P. 9026 - 9026

Published: Aug. 20, 2024

Colorectal cancer (CRC) continues to be a significant contributor global morbidity and mortality. Emerging evidence indicates that disturbances in gut microbial composition, the formation of reactive oxygen species (ROS), resulting inflammation can lead DNA damage, driving pathogenesis progression CRC. Notably, bacterial metabolites either protect against or contribute oxidative stress by modulating activity antioxidant enzymes influencing signaling pathways govern ROS-induced inflammation. Additionally, microbiota byproducts, when supplemented through probiotics, affect tumor microenvironments enhance treatment efficacy selectively mediate destruction CRC cells. This review aims discuss mechanisms which taxonomical shifts related such as short-chain fatty acids, secondary bile trimethylamine-N-oxide influence ROS concentrations safeguard promote onset inflammation-mediated we focus on role probiotic ROS-mediated both status inflammation, Nrf2-Keap1, NF-κB, NLRP3 mitigate carcinogenesis. Overall, deeper understanding may aid delaying preventing offer new avenues for adjunct, CRC-specific therapeutic interventions immunotherapy.

Language: Английский

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Podocyte Death in Diabetic Kidney Disease: Potential Molecular Mechanisms and Therapeutic Targets

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(16), P. 9035 - 9035

Published: Aug. 20, 2024

Cell deaths maintain the normal function of tissues and organs. In pathological conditions, abnormal activation or disruption cell death often leads to pathophysiological effects. Diabetic kidney disease (DKD), a significant microvascular complication diabetes, is linked high mortality morbidity rates, imposing substantial burden on global healthcare systems economies. Loss detachment podocytes are key changes in progression DKD. This review explores potential mechanisms apoptosis, necrosis, autophagy, pyroptosis, ferroptosis, cuproptosis, podoptosis podocytes, focusing how different modes contribute It recognizes limitations current research presents latest basic clinical studies targeting podocyte pathways Lastly, it focuses future treat DKD, with intention inspiring further development therapeutic strategies.

Language: Английский

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Structure of the CUL1–RBX1–SKP1–FBXO4 SCF ubiquitin ligase complex

Biochemical and Biophysical Research Communications, Journal Year: 2024, Volume and Issue: 735, P. 150811 - 150811

Published: Oct. 11, 2024

Language: Английский

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