ArticleInternational journal of molecular sciences2022
Alpha-1 Antitrypsin Inhibits Tumorigenesis and Progression of Colitis-Associated Colon Cancer through Suppression of Inflammatory Neutrophil-Activated Serine Proteases and IGFBP-3 Proteolysis.
Article in International journal of molecular sciences, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 14 citations in OpenAlex.
- Hepatic drug transporters in pharmacotherapy: mechanisms, therapeutic targeting, and clinical translation.Naunyn-Schmiedeberg's archives of pharmacology · 2026Review
- Neutrophil extracellular traps in colorectal cancer: context-dependent roles from inflammatory carcinogenesis to liver metastasis and therapeutic targeting.Journal of translational medicine · 2026Review
- Beyond chemotherapy: the evolving role of photodynamic therapy in triple-negative breast cancer.Medical oncology (Northwood, London, England) · 2026Review
- A Functional Shift of IGFBP3 in Osteoarthritis: From Cartilage Protection to Disease Promotion.Journal of inflammation research · 2026Review
- Identification and validation of platelet activation-related signatures in ulcerative colitis: a study based on machine learning and single-cell transcriptomic analysis.Frontiers in immunology · 2026Article
- Insulin‑like growth factor in cancer: New perspectives (Review).Molecular medicine reports · 2025Review
- IGFBP3 modulation of tumor pathogenesis and cell signaling pathways (Review).Oncology letters · 2025Review
- Identification and validation of diagnostic alternative splicing events in tumor-educated platelets for non-small cell lung cancer in patients with ground-glass opacity: a multicenter study.Translational lung cancer research · 2025Article
- Neutrophils: From Inflammatory Bowel Disease to Colitis-Associated Colorectal Cancer.Journal of inflammation research · 2025Review
- The Inhibition of Serine Proteases by Serpins Is Augmented by Negatively Charged Heparin: A Concise Review of Some Clinically Relevant Interactions.International journal of molecular sciences · 2024Review
- Beneficial effects of alpha-1 antitrypsin therapy in a mouse model of colitis-associated colon cancer.BMC cancer · 2023Article
- Pentosan Polysulfate Affords Pleotropic Protection to Multiple Cells and Tissues.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Review
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Authors and funding
7 authors at 1 institution in 2 countries.
Funding
Abstract
Colitis-associated colon cancer (CAC) accompanies the massive infiltration of neutrophils during tumorigenesis and progression of CAC. Depletion of neutrophils in circulation results in significant inhibition of tumor incidence in CAC. However, the underlying mechanisms are largely unclear. In this study, we provide evidence for the crucial involvement of inflammatory neutrophil-activated serine proteases (NSPs) on the dysregulation of the anti-inflammatory and antitumor IGFBP-3/IGFBP-3R signaling axis in CAC using a chronic AOM/DSS mouse model. We also provide preclinical evidence for α1-antitrypsin (AAT) as a preventive and as a therapeutic for CAC. AAT administration not only prevented colitis-associated tumorigenesis but also inhibited established CAC. AOM/DSS treatment results in the significant activation of NSPs, leading to CAC through increased pro-inflammatory cytokines and decreased anti-inflammatory and antitumor IGFBP-3. Collectively, these data suggest that the NSPs proteolyze IGFBP-3, whereas AAT inhibits chronic colonic inflammation-induced NSP activity and subsequently suppresses IGFBP-3 proteolysis. Therefore, the anti-inflammatory and antitumor functions of the IGFBP-3/IGFBP-3R axis are restored. AAT mimicking small peptides also showed their inhibitory effects on NSP-induced IGFBP-3 proteolysis. These results suggest that targeting the NSP-IGFBP-3/IGFBP-3R axis using NSP inhibitors such as AAT and the AAT mimics and IGFBP-3R agonists could lead to novel approaches for the prevention and treatment of CAC.
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