Inhibiting FAK-Paxillin Interaction Reduces Migration and Invadopodia-Mediated Matrix Degradation in Metastatic Melanoma Cells.
Fiche publication
Date publication
avril 2021
Journal
Cancers
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DUJARDIN Denis, Pr LEHMANN Maxime, Dr RONDE Philippe, Dr ZUBER Guy, Pr GIES Jean-Pierre, Dr SICK Emilie
Tous les auteurs :
Mousson A, Legrand M, Steffan T, Vauchelles R, Carl P, Gies JP, Lehmann M, Zuber G, De Mey J, Dujardin D, Sick E, Rondé P
Lien Pubmed
Résumé
The nonreceptor tyrosine kinase FAK is a promising target for solid tumor treatment because it promotes invasion, tumor progression, and drug resistance when overexpressed. Investigating the role of FAK in human melanoma cells, we found that both in situ and metastatic melanoma cells strongly express FAK, where it controls tumor cells' invasiveness by regulating focal adhesion-mediated cell motility. Inhibiting FAK in human metastatic melanoma cells with either siRNA or a small inhibitor targeting the kinase domain impaired migration but led to increased invadopodia formation and extracellular matrix degradation. Using FAK mutated at Y397, we found that this unexpected increase in invadopodia activity is due to the lack of phosphorylation at this residue. To preserve FAK-Src interaction while inhibiting pro-migratory functions of FAK, we found that altering FAK-paxillin interaction, with either FAK mutation in the focal adhesion targeting (FAT) domain or a competitive inhibitor peptide mimicking paxillin LD domains drastically reduces cell migration and matrix degradation by preserving FAK activity in the cytoplasm. In conclusion, our data show that targeting FAK-paxillin interactions could be a potential therapeutic strategy to prevent metastasis formation, and molecules targeting this interface could be alternative to inhibitors of FAK kinase activity which display unexpected effects.
Mots clés
FAK, invadopodia, melanoma, migration, paxillin, tyrosine kinase inhibitor
Référence
Cancers (Basel). 2021 Apr 14;13(8):