Year: 2020
Type: article
Abstract: is the most frequently mutated oncogene. Here, we demonstrate that a subset of flavaglines, a class of natural anti-tumour drugs and chemical ligands of prohibitins, inhibit RAS GTP loading and oncogene activation in cells at nanomolar concentrations. Treatment with rocaglamide, the first discovered flavagline, inhibited the nanoclustering of KRAS, but not HRAS and NRAS, at specific phospholipid-enriched plasma membrane domains. We further demonstrate that plasma membrane-associated prohibitins directly interact with KRAS, phosphatidylserine and phosphatidic acid, and these interactions are disrupted by rocaglamide but not by the structurally related flavagline FL1. Depletion of prohibitin-1 phenocopied the rocaglamide-mediated effects on KRAS activation and stability. We also demonstrate that flavaglines inhibit the oncogenic growth of KRAS-mutated cells and that treatment with rocaglamide reduces non-small-cell lung carcinoma (NSCLC) tumour nodules in autochthonous KRAS-driven mouse models without severe side effects. Our data suggest that it will be promising to further develop flavagline derivatives as specific KRAS inhibitors for clinical applications
Source: Journal of Cell Science
DOI: 10.1242/jcs.244111
Institutions: Johannes Gutenberg University Mainz, University Medical Center of the Johannes Gutenberg University Mainz, Nanyang Technological University, Åbo Akademi University, Turku Centre for Biotechnology, The University of Texas Health Science Center at Houston, Centre National de la Recherche Scientifique, Université de Strasbourg, University of Luxembourg
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Awards: G1385172195, G327084907
OpenAlex ID: W3026401933