Adhesion- and stress-related adaptation of glioma radiochemoresistance is circumvented by β1 integrin/JNK co-targeting

Oncotarget
Anne VehlowNils Cordes

Abstract

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...Continue Reading

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Citations

Feb 22, 2018·Glia·Valéria Pereira FerrerRolf Mentlein
Jul 12, 2018·Journal of Cell Science·Pavlo G Gritsenko, Peter Friedl
Dec 28, 2018·Nucleic Acids Research·Kate LiddiardDuncan M Baird
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May 28, 2021·International Journal of Clinical Oncology·Tzu-Ju ChenHong-Yue Lai
Jun 3, 2021·International Journal of Molecular Sciences·Bo Young JeongHoi Young Lee
Sep 6, 2021·International Journal of Radiation Oncology, Biology, Physics·Josephine GörteNils Cordes

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Methods Mentioned

BETA
X-ray
acetylation
dot blots
mechanical dissociation
FACS

Clinical Trials Mentioned

NCT01630252

Software Mentioned

Prism
FlowJo
GraphPad
Cytoscape
Excel
Axiovision ( LE )

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