The cytotoxicity of gomesin peptides is mediated by the glycosphingolipid pathway and lipid-cholesterol interactions
Gomesins (AgGom and HiGom) are therapeutically promising spider-derived peptides that target a specific phospholipid composition (3PC:1PS:1Chol) to disrupt melanoma cell membranes and induce cytotoxicity. Their antiproliferative properties are interrelated to lipid metabolism, particularly glycosphingolipid biosynthesis. We used lipidomics, CRISPR/Cas9 knockout screening, molecular and biophysical experiments, followed by xenograft melanoma animal studies to demonstrate that gomesins target the glycosphingolipid pathway via inhibition of the ST3GAL5 gene. Notably, the addition of cholesterol reduced the cytotoxicity of gomesins, which may explain why melanoma cells with lower cholesterol levels than neonatal foreskin fibroblasts are more sensitive to gomesins. We propose that gomesins bind to melanoma CRAC domains, restricting intracellular cholesterol and thereby enhancing their cytotoxicity. In line with this hypothesis, cholesterol sequestration and the disruption of lipid raft microdomains enhanced the cytotoxic effects of gomesins in melanoma cells, whereas adding cholesterol in membrane permeability and proliferation assays reduced the effects of gomesin treatment. Taken together, this study highlights the specific role of cholesterol and the glycosphingolipid pathway in melanoma cells, paving the way for new strategies in targeted melanoma therapies.
Authors
- Sergey Kurdyukov (ORCID: https://orcid.org/0000-0001-5824-0443)
- Thomas Kremsmayr (ORCID: https://orcid.org/0000-0003-0630-2555)
- Felicity Chung
- Sara C. Novais (ORCID: https://orcid.org/0000-0003-1306-3396)
- G. Gregory Neely (ORCID: https://orcid.org/0000-0002-1957-9732)
- Naomi McKinnon
- Gregor Anderluh (ORCID: https://orcid.org/0000-0002-9916-8465)
- Manuel A. Fernández‐Rojo (ORCID: https://orcid.org/0000-0002-2240-1951)
- F. Castejón (ORCID: https://orcid.org/0000-0002-4654-0542)
- Jan Procházka (ORCID: https://orcid.org/0000-0003-4675-8995)
- Evelyne Deplazes (ORCID: https://orcid.org/0000-0003-2052-5536)
- Maria P. Ikonomopoulou (ORCID: https://orcid.org/0000-0001-7739-080X)
- Javier Moral‐Sanz (ORCID: https://orcid.org/0000-0001-8602-8554)
- Kristina Eleršič (ORCID: https://orcid.org/0000-0002-0868-2603)
- Markus Muttenthaler (ORCID: https://orcid.org/0000-0003-1996-4646)
- Zoltan Dekan (ORCID: https://orcid.org/0000-0002-6841-4176)
- Paul F. Alewood (ORCID: https://orcid.org/0000-0001-7454-6522)
- Èlia Òbis (ORCID: https://orcid.org/0000-0002-6838-1634)
- Mariona Jové (ORCID: https://orcid.org/0000-0001-5577-6162)
- Reinald Pamplona (ORCID: https://orcid.org/0000-0003-4337-6107)
- Lissy M. Hartmann (ORCID: https://orcid.org/0000-0003-1933-1777)
- Isabel Fernández‐Carrasco
- Bernhard Jandl (ORCID: https://orcid.org/0000-0003-1383-9713)
- Matthew A. Waller (ORCID: https://orcid.org/0000-0001-5748-9159)
- Daniel P. Rainho (ORCID: https://orcid.org/0009-0002-2361-9319)
Institutions
- Madrid Institute for Advanced Studies (ES)
- University of Technology Sydney (AU)
- The University of Sydney (AU)
- University of Vienna (AT)
- Translational Research Institute (AU)
- Universitat de Lleida (ES)
- The University of Queensland (AU)
- Instituto de Investigación Biomédica de Lleida (ES)
- Czech Academy of Sciences, Institute of Molecular Genetics (CZ)
- National Institute of Chemistry (SI)
Publication Details
- Journal
- Cell Death Discovery
- Published
- 2025-11-21
- DOI
- https://doi.org/10.1038/s41420-025-02817-x
- Primary Topic
- Antimicrobial Peptides and Activities
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- QIMR Berghofer Medical Research Institute
- European Commission
- Medical Research Council
- National Health and Medical Research Council
- Agència de Gestió d'Ajuts Universitaris i de Recerca
- European Regional Development Fund
- Agencia Estatal de Investigación