A subset of flavaglines inhibits KRAS nanoclustering and activation.
Fiche publication
Date publication
mai 2020
Journal
Journal of cell science
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DESAUBRY Laurent
Tous les auteurs :
Yurugi H, Zhuang Y, Siddiqui FA, Liang H, Rosigkeit S, Zeng Y, Abou-Hamdan H, Bockamp E, Zhou Y, Abankwa D, Zhao W, Désaubry L, Rajalingam K
Lien Pubmed
Résumé
RAS oncogenes are frequently mutated in human cancers and among the three isoforms (KRAS, HRAS and NRAS), KRAS 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, phosphatidyl serine and phosphatidic acid, and these interactions are disrupted by rocaglamide but not by a structurally related flavagline FL1. Depletion of prohibitin-1 phenocopied rocaglamide-mediated effects on RAS activation and stability. We also demonstrate that flavaglines inhibit the oncogenic growth of KRAS-mutated cells and treatment with rocaglamide reduces NSCLC tumours 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.
Mots clés
Flavagline, Kras, Lipid nanocluster, Phospholipid, Prohibitin, Rocaglamide
Référence
J. Cell. Sci.. 2020 May 22;: