Focal adhesion kinase confers pro-migratory and antiapoptotic properties and is a potential therapeutic target in Ewing sarcoma.

Autor: Steinestel K; Gerhard Domagk Institute of Pathology, University Hospital Münster, Germany.; Institute of Pathology and Molecular Pathology, Bundeswehrkrankenhaus Ulm, Germany., Trautmann M; Gerhard Domagk Institute of Pathology, University Hospital Münster, Germany.; Division of Translational Pathology, Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Germany., Jansen EP; Gerhard Domagk Institute of Pathology, University Hospital Münster, Germany., Dirksen U; Pediatrics III, West German Cancer Centre, University Hospital Essen, Germany., Rehkämper J; Institute of Pathology, University Hospital Cologne, Germany., Mikesch JH; Department of Medicine A, University Hospital Münster, Germany., Gerke JS; Max Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Germany., Orth MF; Max Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Germany., Sannino G; Max Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Germany., Arteaga MF; Department of Medicine A, University Hospital Münster, Germany., Rossig C; Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, Germany., Wardelmann E; Gerhard Domagk Institute of Pathology, University Hospital Münster, Germany., Grünewald TGP; Max Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Germany.; German Cancer Consortium (DKTK), Partner Site Munich, Germany.; German Cancer Research Center (DKFZ), Heidelberg, Germany.; Institute of Pathology, Faculty of Medicine, LMU Munich, Germany., Hartmann W; Gerhard Domagk Institute of Pathology, University Hospital Münster, Germany.; Division of Translational Pathology, Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Germany.
Jazyk: angličtina
Zdroj: Molecular oncology [Mol Oncol] 2020 Feb; Vol. 14 (2), pp. 248-260. Date of Electronic Publication: 2019 Dec 21.
DOI: 10.1002/1878-0261.12610
Abstrakt: Oncogenesis of Ewing sarcoma (EwS), the second most common malignant bone tumor of childhood and adolescence, is dependent on the expression of chimeric EWSR1-ETS fusion oncogenes, most often EWSR1-FLI1 (E/F). E/F expression leads to dysregulation of focal adhesions (FAs) enhancing the migratory capacity of EwS cells. Here, we show that, in EwS cell lines and tissue samples, focal adhesion kinase (FAK) is expressed and phosphorylated at Y397 in an E/F-dependent way involving Ezrin. Employing different EwS cell lines as in vitro models, we found that key malignant properties of E/F are mediated via substrate-independent autophosphorylation of FAK on Y397. This phosphorylation results in enhanced FA formation, Rho-dependent cell migration, and impaired caspase-3-mediated apoptosis in vitro. Conversely, treatment with the FAK inhibitor 15 (1,2,4,5-benzenetetraamine tetrahydrochloride (Y15) enhanced caspase-mediated apoptosis and EwS cell migration, independent from the respective EWSR1-ETS fusion type, mimicking an anoikis-like phenotype and paralleling the effects of FAK siRNA knockdown. Our findings were confirmed in vivo using an avian chorioallantoic membrane model and provide a first rationale for the therapeutic use of FAK inhibitors to impair metastatic dissemination of EwS.
(© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)
Databáze: MEDLINE
Externí odkaz: