The cytotoxicity of gomesin peptides is mediated by the glycosphingolipid pathway and lipid-cholesterol interactions
Year: 2025
Type: article
Abstract: 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.
Source: Cell Death Discovery
Authors: Isabel Fernandez-Carrasco, Javier Moral-Sanz, Sergey Kurdyukov, Èlia Obis, Lissy Maike Hartmann, Silvia Carina Magalhães Novais, Matthew A. Waller, Naomi McKinnon, Felicity Chung, Francisco Javier Salazar Castejón, Daniel P. Rainho, Zoltan Dekan, Thomas Kremsmayr, Bernhard Jandl, Kristina Eleršič Filipič, Reinald Pamplona, Mariona Jové, Manuel A. Fernandez-Rojo, Gregor Anderluh, Markus Muttenthaler, Paul F. A. Alewood, Jan Procházka, G. Gregory Neely, Evelyne Deplazes, Maria P. Ikonomopoulou
Institutions: Madrid Institute for Advanced Studies, The University of Sydney, Universitat de Lleida, Instituto de Investigación Biomédica de Lleida, The University of Queensland, Czech Academy of Sciences, Czech Academy of Sciences, Institute of Molecular Genetics, Czech Centre for Phenogenomics, Institute for Molecular Bioscience, University of Vienna, National Institute of Chemistry, Translational Research Institute, University of Technology Sydney
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,690
Funders: QIMR Berghofer Medical Research Institute, European Commission, European Cooperation in Science and Technology, Medical Research Council, Australian 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, HORIZON EUROPE European Research Council
Awards: Theranostic Peptide Tracers for Breast Cancer, G337421212, G3480869486, G6033112984, Intestinal Biofilms – New opportunities in diagnosing and treating gut disorders, Molecular probe development for high specificity and spatiotemporal control, G7084143925, G7334572374, Venom-derived blood-brain-barrier shuttles
OpenAlex ID: W4416501429