Adhesion-and stress-related adaptation of Glioma radiochemoresistance is circumvented by beta 1 integrin/JNK cotargeting

作者：Vehlow Anne; Klapproth Erik; Storch Katja; Dickreuter Ellen; Seifert Michael; Dietrich Antje; Buetof Rebecca; Temme Achim; Cordes Nils^*

来源：Oncotarget, 2017, 8(30): 49224-49237.

DOI：10.18632/oncotarget.17480

• beta 1 integrin
• JNK
• radiochemoresistance
• GBM stem-like cells
• orthotopic GBM mouse model

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 beta 1 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 beta 1 integrin/JNK co-inhibition are superior to the monotherapy. Mechanistically, the in vitro radiosensitization provoked by beta 1 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 beta 1 integrin/JNK co-dependent bypass signaling for GBM therapy resistance, which might be therapeutically exploitable.

• 出版日期2017-7-25
• 单位河北医科大学