ArticleExperimental & molecular medicine2025
SLC6A14-mediated glutamine promotes SYTL4-CXCL8 axis activation to drive gemcitabine resistance and immune evasion in pancreatic cancer.
Article in Experimental & molecular medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Unveiling the Diagnostic Value and Potential Therapeutic Targets of Phenylalanine Metabolism in Pancreatic Cancer via Integrated Multi-Omics and Machine Learning.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Emerging roles of SLC6A14 in digestive system diseases: from amino acid transport to therapeutic targeting.Molecular biology reports · 2026Review
- A novel glutamine metabolism-based classification system for characterizing the heterogeneity of hepatocellular carcinoma.Journal of gastrointestinal oncology · 2026Article
- Metabolic pattern changes of macrophages during cancer development and progression.Journal of translational medicine · 2026Review
- Advances in Biological Functions and Applications of Feeding Microorganism-derived Extracellular Vesicles.Probiotics and antimicrobial proteins · 2026Review
- The molecular network in bacteria responsible for the mitigation of salinity stress.World journal of microbiology & biotechnology · 2026Review
- Computational-experimental identification of bioactive component combinations from Salvia miltiorrhiza for cardiovascular protection.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Metabolic immune checkpoints in cancer: how tumor-derived metabolites shape immunotherapy resistance.Frontiers in immunology · 2026Review
- Peritoneal metastasis in pancreatic cancer: molecular mechanisms, microenvironmental remodeling, and emerging intraperitoneal interventions.Frontiers in molecular biosciences · 2026Review
- Phosphoenolpyruvate carboxykinase 2 (PCK2) attenuates bovine adipocyte lipolysis through PNPLA2 activity repression.Functional & integrative genomics · 2025Article
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10 authors.
Funding
Abstract
Chemoresistance remains a major challenge in pancreatic ductal adenocarcinoma (PDAC). Glutamine sustains drug resistance and shapes the immunosuppressive tumor microenvironment; however, the underlying mechanisms remain unclear. Identifying key regulators that drive both gemcitabine resistance and immune evasion is crucial for improving theapeutic outcomes in PDAC. Here we identified solute-carrier family 6 member 14 (SLC6A14) as the central regulator of glutamine metabolism that drives gemcitabine resistance. SLC6A14-mediated glutamine metabolism facilitated α-ketoglutarate production, activating mTOR/NF-κB signaling to upregulate PD-L1 expression, playing a central role in immune evasion. Moreover, SLC6A14 induced CXC motif chemokine ligand 8 secretion via synaptotagmin-like 4-mediated exocytosis, paracrinally activating CXCR2 signaling in cancer-associated fibroblasts to enhance mitochondrial fission and amino acid recycling, supporting PDAC progression. Targeting SLC6A14 with α-methyl-tryptophan enhanced gemcitabine sensitivity, suppressed PD-L1 driven immune evasion and reduced tumor growth, metastasis and glutamine production in vivo. These findings underscore SLC6A14 as a pivtoal mediator of glutamine-driven gemcitabine resistance and immune evasion in PDAC. Therapeutic strategies targeting SLC6A14, either alone or in combination with PD-L1 blockade, hold promise for overcoming chemoresistance and enhancing antitumor immunity in gemcitabine-resistant pancreatic cancer.
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