Targeting prohibitins with chemical ligands inhibits KRAS-mediated lung tumours.
Fiche publication
Date publication
avril 2017
Journal
Oncogene
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DESAUBRY Laurent
Tous les auteurs :
Yurugi H, Marini F, Weber C, David K, Zhao Q, Binder H, Désaubry L, Rajalingam K
Lien Pubmed
Résumé
KRAS is one of the most frequently mutated oncogenes in human non-small cell lung cancers (NSCLCs). RAS proteins trigger multiple effector signalling pathways including the highly conserved RAF-MAPK pathway. CRAF, a direct RAS effector protein, is required for KRAS-mediated tumourigenesis. Thus, the molecular mechanisms driving the activation of CRAF are intensively studied. Prohibitin 1 (PHB1) is an evolutionarily conserved adaptor protein and interaction of CRAF with PHB1 at the plasma membrane is essential for CRAF activation. Here, we demonstrate that PHB1 is highly expressed in NSCLC patients and correlates with poor survival. Targeting of PHB1 with two chemical ligands (rocaglamide and fluorizoline) inhibits epidermal growth factor (EGF)/RAS-induced CRAF activation. Consistently, treatment with rocaglamide inhibited proliferation, migration and anchorage-independent growth of KRAS-mutated lung carcinoma cell lines. Surprisingly, rocaglamide treatment inhibited Ras-GTP loading in KRAS-mutated cells as well as in EGF-stimulated cells. Rocaglamide treatment further prevented the oncogenic growth of KRAS-driven lung cancer allografts and xenografts in mouse models. Our results suggest rocaglamide as a RAS inhibitor and that targeting plasma membrane-associated PHB1 with chemical ligands would be a viable therapeutic strategy to combat KRAS-mediated NSCLCs.Oncogene advance online publication, 17 April 2017; doi:10.1038/onc.2017.93.
Mots clés
Animals, Benzofurans, administration & dosage, Carcinoma, Non-Small-Cell Lung, drug therapy, Cell Line, Tumor, Cell Proliferation, EGF Family of Proteins, metabolism, Gene Expression Regulation, Neoplastic, Humans, Ligands, Lung Neoplasms, drug therapy, Mice, Mice, Knockout, Molecular Targeted Therapy, Proto-Oncogene Proteins p21(ras), genetics, Repressor Proteins, antagonists & inhibitors, Signal Transduction, TNF Receptor-Associated Factor 3, metabolism, Xenograft Model Antitumor Assays, raf Kinases, metabolism, ras Proteins, antagonists & inhibitors
Référence
Oncogene. 2017 Apr;: