Adhesion- and stress-related adaptation of glioma radiochemoresistance is circumvented by β1 integrin/JNK co-targeting
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Anne Vehlow1,2,10,11, Erik Klapproth1, Katja Storch1,3, Ellen Dickreuter1, Michael Seifert4,5, Antje Dietrich1,8,9, Rebecca Bütof1,5,6,8,9, Achim Temme7,8,9 and Nils Cordes1,3,6,8,9
1OncoRay, National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden, Rossendorf, PF 41, 01307, Dresden, Germany
2Helmholtz-Zentrum Dresden, Rossendorf, Institute of Radiopharmaceutical Cancer Research, 01328, Dresden, Germany
3Helmholtz-Zentrum Dresden, Rossendorf, Institute of Radiooncology, OncoRay, 01328, Dresden, Germany
4Institute for Medical Informatics and Biometry, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307, Dresden, Germany
5National Center for Tumor Diseases (NCT), Partner Site Dresden, 69192, Heidelberg, Germany
6Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, PF 50, 01307, Dresden, Germany
7Department of Neurosurgery, Section of Experimental Neurosurgery/Tumor Immunology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307, Dresden, Germany
8German Cancer Consortium (DKTK), Parter Site Dresden, 69192, Heidelberg, Germany
9German Cancer Research Center (DKFZ), 69192, Heidelberg, Germany
10Current address: National Center for Tumor Diseases (NCT), Partner Site Dresden, 69192, Heidelberg, Germany
11Current address: German Cancer Consortium (DKTK), Parter Site Dresden, and German Cancer Research Center (DKFZ), 69192, Heidelberg, Germany
Nils Cordes, email: [email protected]
Keywords: β1 integrin, JNK, radiochemoresistance, GBM stem-like cells, orthotopic GBM mouse model
Received: February 24, 2017 Accepted: April 12, 2017 Published: April 27, 2017
Resistance of cancer stem-like and cancer tumor bulk cells to radiochemotherapy and destructive infiltration of the brain fundamentally influence the treatment efficiency to cure of patients suffering from Glioblastoma (GBM). The interplay of adhesion and stress-related signaling and activation of bypass cascades that counteract therapeutic approaches remain to be identified in GBM cells. We here show that combined inhibition of the adhesion receptor β1 integrin and the stress-mediator c-Jun N-terminal kinase (JNK) induces radiosensitization and blocks invasion in stem-like and patient-derived GBM cultures as well as in GBM cell lines. In vivo, this treatment approach not only significantly delays tumor growth but also increases median survival of orthotopic, radiochemotherapy-treated GBM mice. Both, in vitro and in vivo, effects seen with β1 integrin/JNK co-inhibition are superior to the monotherapy. Mechanistically, the in vitro radiosensitization provoked by β1 integrin/JNK targeting is caused by defective DNA repair associated with chromatin changes, enhanced ATM phosphorylation and prolonged G2/M cell cycle arrest. Our findings identify a β1 integrin/JNK co-dependent bypass signaling for GBM therapy resistance, which might be therapeutically exploitable.
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