{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T18:54:53Z","timestamp":1772736893491,"version":"3.50.1"},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T00:00:00Z","timestamp":1770854400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Association \u201cCANCEN,\u201d the Institut National du Cancer","award":["INCa-PLBIO18-151"],"award-info":[{"award-number":["INCa-PLBIO18-151"]}]},{"DOI":"10.13039\/501100004281","name":"National Science Centre of Poland","doi-asserted-by":"crossref","award":["UMO-2023\/49\/B\/ST4\/00041"],"award-info":[{"award-number":["UMO-2023\/49\/B\/ST4\/00041"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P41GM103390"],"award-info":[{"award-number":["P41GM103390"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HLBI R01HL151617"],"award-info":[{"award-number":["HLBI R01HL151617"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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.<\/jats:p>","DOI":"10.1093\/glycob\/cwag010","type":"journal-article","created":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T12:27:34Z","timestamp":1770726454000},"source":"Crossref","is-referenced-by-count":0,"title":["Structural determinants of glycosaminoglycan oligosaccharides as LL-37 inhibitors in breast cancer"],"prefix":"10.1093","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-7890-9808","authenticated-orcid":false,"given":"Chloe","family":"Le Fournis","sequence":"first","affiliation":[{"name":"Universit\u00e9 de Tours , Inserm UMR1069 N2COx, 10 Boulevard Tonnelle\u0301, 37032 Tours ,","place":["France"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1206-5624","authenticated-orcid":false,"given":"Martyna","family":"Maszota-Zieleniak","sequence":"additional","affiliation":[{"name":"Department of Theoretical Chemistry, Faculty of Chemistry, University of Gda\u0144sk , ul. Wita Stwosza 63, 80-308, Gda\u0144sk ,","place":["Poland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam","family":"Kulesza","sequence":"additional","affiliation":[{"name":"Department of Theoretical Chemistry, Faculty of Chemistry, University of Gda\u0144sk , ul. Wita Stwosza 63, 80-308, Gda\u0144sk ,","place":["Poland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6003-4574","authenticated-orcid":false,"given":"Pradeep","family":"Chopra","sequence":"additional","affiliation":[{"name":"Complex Carbohydrate Research Center, University of Georgia , 315 Riverbend Rd, Athens, GA 30602 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3111-5954","authenticated-orcid":false,"given":"Geert-Jan","family":"Boons","sequence":"additional","affiliation":[{"name":"Complex Carbohydrate Research Center, University of Georgia , 315 Riverbend Rd, Athens, GA 30602 ,","place":["United States"]},{"name":"Department of Chemistry, University of Georgia , 312 East Campus Road, Suite 1299B, Athens, GA 30602,","place":["United States"]},{"name":"Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Bijvoet Center for Biomolecular Research, Utrecht University , Universiteitsweg 99, 3584 CG Utrecht ,","place":["The Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicolas","family":"Aubrey","sequence":"additional","affiliation":[{"name":"UMR 1282 ISP, INRAE, Universit\u00e9 de Tours , Team BioMAP, 37200 Tours ,","place":["France"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8359-2966","authenticated-orcid":false,"given":"Franziska","family":"Liesecke","sequence":"additional","affiliation":[{"name":"Department of Plant Biology, Swedish University of Agricultural Sciences , Almas All\u00e9 8, 75007 Uppsala ,","place":["Sweden"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5166-4849","authenticated-orcid":false,"given":"Sergey A","family":"Samsonov","sequence":"additional","affiliation":[{"name":"Department of Theoretical Chemistry, Faculty of Chemistry, University of Gda\u0144sk , ul. Wita Stwosza 63, 80-308, Gda\u0144sk ,","place":["Poland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3861-808X","authenticated-orcid":false,"given":"G\u00fcnther","family":"Weber","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Tours , Inserm UMR1069 N2COx, 10 Boulevard Tonnelle\u0301, 37032 Tours ,","place":["France"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2026,2,12]]},"reference":[{"key":"2026030512564269800_ref1","doi-asserted-by":"publisher","DOI":"10.13140\/RG.2.2.25321.36969","volume-title":"Amber","author":"Case","year":"2020"},{"issue":"3","key":"2026030512564269800_ref2","doi-asserted-by":"publisher","first-page":"1060","DOI":"10.1159\/000490183","article-title":"Roles and mechanisms of human cathelicidin LL-37 in cancer","volume":"47","author":"Chen","year":"2018","journal-title":"Cell Physiol Biochem"},{"key":"2026030512564269800_ref3","doi-asserted-by":"publisher","first-page":"119734","DOI":"10.1016\/j.carbpol.2022.119734","article-title":"Binding of heparan sulfate to human cystatin C modulates inhibition of cathepsin L\u00a0: putative consequences in mucopolysaccharidosis","volume":"293","author":"Denamur","year":"2022","journal-title":"Carbohydr Polym"},{"issue":"2","key":"2026030512564269800_ref4","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1007\/s12551-025-01309-7","article-title":"Selectivity of membrane-active peptides\u00a0: the role of electrostatics and other membrane biophysical properties","volume":"17","author":"Felsztyna","year":"2025","journal-title":"Biophys Rev"},{"issue":"43","key":"2026030512564269800_ref5","doi-asserted-by":"publisher","first-page":"36132","DOI":"10.1074\/jbc.M112.384875","article-title":"Endothelial heparan Sulfate 6-O-sulfation levels regulate angiogenic responses of endothelial cells to fibroblast growth factor 2 and vascular endothelial growth factor","volume":"287","author":"Ferreras","year":"2012","journal-title":"J Biol Chem"},{"issue":"17","key":"2026030512564269800_ref6","doi-asserted-by":"publisher","first-page":"23785","DOI":"10.18632\/oncotarget.8122","article-title":"Activation of TRPV2 and BKCa channels by the LL-37 enantiomers stimulates calcium entry and migration of cancer cells","volume":"7","author":"Gambade","year":"2016","journal-title":"Oncotarget"},{"issue":"9","key":"2026030512564269800_ref7","doi-asserted-by":"publisher","first-page":"481","DOI":"10.3390\/biom9090481","article-title":"Sulfated Glycoaminoglycans and proteoglycan Syndecan-4 are involved in membrane fixation of LL-37 and its pro-migratory effect in breast cancer cells","volume":"9","author":"Habes","year":"2019","journal-title":"Biomolecules"},{"issue":"5","key":"2026030512564269800_ref8","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1002\/ijc.20795","article-title":"Antimicrobial protein hCAP18\/LL-37 is highly expressed in breast cancer and is a putative growth factor for epithelial cells","volume":"114","author":"Heilborn","year":"2005","journal-title":"Int J Cancer"},{"key":"2026030512564269800_ref9","doi-asserted-by":"publisher","first-page":"1871","DOI":"10.3389\/fimmu.2018.01871","article-title":"Host Defense peptide LL-37-mediated chemoattractant properties, but not anti-inflammatory cytokine IL-1RA production, is selectively controlled by Cdc42 rho GTPase via G protein-coupled receptors and JNK mitogen-activated protein kinase","volume":"9","author":"Hemshekhar","year":"2018","journal-title":"Front Immunol"},{"issue":"21","key":"2026030512564269800_ref10","doi-asserted-by":"publisher","first-page":"6545","DOI":"10.1021\/bi0273563","article-title":"Mechanism of lipid bilayer disruption by the human antimicrobial peptide, LL-37","volume":"42","author":"Henzler Wildman","year":"2003","journal-title":"Biochemistry"},{"issue":"26","key":"2026030512564269800_ref11","doi-asserted-by":"publisher","first-page":"8459","DOI":"10.1021\/bi036284s","article-title":"Perturbation of the hydrophobic Core of lipid bilayers by the human antimicrobial peptide LL-37","volume":"43","author":"Henzler-Wildman","year":"2004","journal-title":"Biochemistry"},{"issue":"1","key":"2026030512564269800_ref12","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD\u00a0: visual molecular dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J Mol Graph"},{"issue":"6","key":"2026030512564269800_ref13","doi-asserted-by":"publisher","first-page":"152025","DOI":"10.1016\/j.imbio.2020.152025","article-title":"IL-33 synergistically promotes the proliferation of lung cancer cells in vitro by inducing antibacterial peptide LL-37 and proinflammatory cytokines in macrophages","volume":"225","author":"Jiang","year":"2020","journal-title":"Immunobiology"},{"issue":"30","key":"2026030512564269800_ref14","doi-asserted-by":"publisher","first-page":"20891","DOI":"10.1021\/jacs.4c05377","article-title":"Antimicrobial peptides increase line tension in raft-forming lipid membranes","volume":"146","author":"Koynarev","year":"2024","journal-title":"J Am Chem Soc"},{"key":"2026030512564269800_ref15","doi-asserted-by":"publisher","first-page":"122294","DOI":"10.1016\/j.carbpol.2024.122294","article-title":"Glycosaminoglycans exhibit distinct interactions and signaling with BMP2 according to their nature and localization","volume":"341","author":"Le Pennec","year":"2024","journal-title":"Carbohydr Polym"},{"issue":"6","key":"2026030512564269800_ref16","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.1021\/acscentsci.1c00010","article-title":"Heparan Sulfate proteoglycans as attachment factor for SARS-CoV-2","volume":"7","author":"Liu","year":"2021","journal-title":"ACS Central Science"},{"issue":"1","key":"2026030512564269800_ref17","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1097\/MOH.0b013e32831ac517","article-title":"The roles of cathelicidin LL-37 in immune defences and novel clinical applications","volume":"16","author":"Nijnik","year":"2009","journal-title":"Curr Opin Hematol"},{"issue":"1","key":"2026030512564269800_ref18","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1007\/s00005-015-0359-5","article-title":"The role of cathelicidin LL-37 in cancer development","volume":"64","author":"Piktel","year":"2016","journal-title":"Arch Immunol Ther Exp"},{"key":"2026030512564269800_ref19","volume-title":"A language and environment for statistical computing","author":"R Core Team","year":"2024"},{"issue":"49","key":"2026030512564269800_ref20","doi-asserted-by":"publisher","first-page":"10486","DOI":"10.1021\/bi1011749","article-title":"Interaction of human \u03b2-defensin 2 (HBD2) with glycosaminoglycans","volume":"49","author":"Seo","year":"2010","journal-title":"Biochemistry"},{"issue":"25","key":"2026030512564269800_ref21","doi-asserted-by":"publisher","first-page":"15421","DOI":"10.1074\/jbc.M115.655845","article-title":"The interaction of heparin Tetrasaccharides with chemokine CCL5 is modulated by sulfation pattern and pH","volume":"290","author":"Singh","year":"2015","journal-title":"J Biol Chem"},{"issue":"11","key":"2026030512564269800_ref22","doi-asserted-by":"publisher","first-page":"e50078","DOI":"10.1371\/journal.pone.0050078","article-title":"LL-37 induces polymerization and bundling of actin and affects actin structure","volume":"7","author":"Sol","year":"2012","journal-title":"PLoS One"},{"issue":"4","key":"2026030512564269800_ref23","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1016\/j.bbamem.2007.11.016","article-title":"Binding of LL-37 to model biomembranes\u00a0: insight into target vs host cell recognition","volume":"1778","author":"Sood","year":"2008","journal-title":"Biochim Biophys Acta"},{"key":"2026030512564269800_ref24","doi-asserted-by":"publisher","first-page":"113703","DOI":"10.1016\/j.ab.2020.113703","article-title":"An improved barium-rhodizonate method for determination of sulfate ion in biological fluids","volume":"598","author":"Su","year":"2020","journal-title":"Anal Biochem"},{"issue":"2","key":"2026030512564269800_ref25","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1016\/0003-2697(71)90167-9","article-title":"Method for determination of the sulfate content of glycosaminoglycans","volume":"41","author":"Terho","year":"1971","journal-title":"Anal Biochem"},{"issue":"8","key":"2026030512564269800_ref26","doi-asserted-by":"publisher","first-page":"e0183542","DOI":"10.1371\/journal.pone.0183542","article-title":"LL-37 causes cell death of human nasal epithelial cells, which is inhibited with a synthetic glycosaminoglycan","volume":"12","author":"Thomas","year":"2017","journal-title":"PLoS One"},{"issue":"45","key":"2026030512564269800_ref27","doi-asserted-by":"publisher","first-page":"30471","DOI":"10.1074\/jbc.M802185200","article-title":"The human cathelicidin LL-37 modulates the activities of the P2X7 receptor in a structure-dependent manner","volume":"283","author":"Tomasinsig","year":"2008","journal-title":"J Biol Chem"},{"issue":"2","key":"2026030512564269800_ref28","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1016\/j.carbpol.2010.08.020","article-title":"Can the interaction between the antimicrobial peptide LL-37 and alginate be exploited for the formulation of new biomaterials with antimicrobial properties?","volume":"83","author":"Toppazzini","year":"2011","journal-title":"Carbohydr Polym"},{"issue":"3","key":"2026030512564269800_ref29","doi-asserted-by":"publisher","first-page":"1442","DOI":"10.4049\/jimmunol.1000376","article-title":"LL-37 directs macrophage differentiation toward macrophages with a proinflammatory signature","volume":"185","author":"Van Der Does","year":"2010","journal-title":"J Immunol"},{"key":"2026030512564269800_ref30","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.peptides.2016.09.002","article-title":"Molecular mechanisms of LL-37-induced receptor activation: an overview","volume":"85","author":"Verjans","year":"2016","journal-title":"Peptides"},{"issue":"1","key":"2026030512564269800_ref31","doi-asserted-by":"publisher","DOI":"10.1186\/bcr2221","article-title":"Human antimicrobial protein hCAP18\/LL-37 promotes a metastatic phenotype in breast cancer","volume":"11","author":"Weber","year":"2009","journal-title":"Breast Cancer Res"},{"issue":"8","key":"2026030512564269800_ref32","doi-asserted-by":"publisher","first-page":"1741","DOI":"10.1002\/ijc.25489","article-title":"Emerging roles of the host defense peptide LL-37 in human cancer and its potential therapeutic applications","volume":"127","author":"Wu","year":"2010","journal-title":"Int J Cancer"},{"issue":"1","key":"2026030512564269800_ref33","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1186\/s13287-016-0313-4","article-title":"LL-37 stimulates the functions of adipose-derived stromal\/stem cells via early growth response 1 and the MAPK pathway","volume":"7","author":"Yang","year":"2016","journal-title":"Stem Cell Res Ther"},{"issue":"4","key":"2026030512564269800_ref34","doi-asserted-by":"publisher","first-page":"1891","DOI":"10.1167\/iovs.09-3904","article-title":"LL-37 via EGFR transactivation to promote high glucose-attenuated epithelial wound healing in organ-cultured corneas","volume":"51","author":"Yin","year":"2010","journal-title":"Invest Ophthalmol Vis Sci"}],"container-title":["Glycobiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/glycob\/advance-article-pdf\/doi\/10.1093\/glycob\/cwag010\/66856405\/cwag010.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/glycob\/article-pdf\/36\/4\/cwag010\/66856405\/cwag010.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/glycob\/article-pdf\/36\/4\/cwag010\/66856405\/cwag010.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T17:56:49Z","timestamp":1772733409000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/glycob\/article\/doi\/10.1093\/glycob\/cwag010\/8473536"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,12]]},"references-count":34,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,3,3]]}},"URL":"https:\/\/doi.org\/10.1093\/glycob\/cwag010","relation":{},"ISSN":["1460-2423"],"issn-type":[{"value":"1460-2423","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,4]]},"published":{"date-parts":[[2026,2,12]]},"article-number":"cwag010"}}