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Abstract

The human antimicrobial peptide LL-37 exerts a dual role in cancer, promoting tumor progression in breast carcinoma by stimulating calcium influx and enhancing cell migration. Its interactions with glycosaminoglycans (GAGs) provide an attractive therapeutic avenue for intervention. In this study, we investigated the ability of structurally distinct GAG oligosaccharides to inhibit LL-37-mediated responses in MDA-MB-231 breast cancer cells. Functional assays were performed to evaluate membrane depolarization, intracellular calcium mobilization, and migration capacity. When applied at a 1:1 stoichiometric ratio with LL-37, heparin emerged as the most effective inhibitor. This inhibitory activity required a minimum oligosaccharide length of 18 monosaccharide units and was strongly dependent on the degree of sulfation. Heparin displayed significantly higher efficacy than either chondroitin sulfate or dermatan sulfate. Binding studies using microscale thermophoresis demonstrated nanomolar affinity of LL-37 for heparin, whereas interactions with chondroitin and dermatan sulfate were weaker. Complementary molecular dynamics simulations reinforced these findings by highlighting the predominant role of electrostatic interactions in stabilizing LL-37/GAG complexes and by providing atomistic models of the binding interfaces. Binding studies on a heparin-derived synthetic oligosaccharide array revealed that, apart from the degree of sulfation, structural components in heparin contribute to its affinity for LL-37. Collectively, our results suggest that the structural optimization of GAG mimetics may represent a promising targeted strategy to block LL-37-driven tumor progression.

Keywords

breast cancer; glycosaminoglycans; LL-37; metastasis; sulfation code

Published in

Glycobiology
2026, volume: 36, number: 4, article number: cwag010
Publisher: OXFORD UNIV PRESS INC

SLU Authors

UKÄ Subject classification

Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Cancer and Oncology

Publication identifier

  • DOI: https://doi.org/10.1093/glycob/cwag010

Permanent link to this page (URI)

https://res.slu.se/id/publ/146467