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 be therapeutically exploitable.
Highlights
Owing to the radiochemoresistant and infiltrative nature of Glioblastoma (GBM) [1,2,3,4], the prognosis of GBM patients is poor with an estimated five year overall survival of less than five percent [5, 6]
Cancer therapy resistance arises as a result from different factors, mainly genetic alterations in cancer stem or bulk cells, changes in the tumor microenvironment and the plasticity to evade therapeutic intervention by initiation of prosurvival adaptation mechanisms
We show that (i) combined β1 integrin/Jun N-terminal kinase (JNK) targeting induces radiosensitization superior to monotherapies and blocks GBM cell invasion, (ii) inhibition of β1 integrin itself or JNK induces β1 integrin expression putatively acting as part of an adaptation mechanism, (iii) simultaneous www.impactjournals.com/oncotarget targeting of β1 integrin and JNK in combination with radiotherapy/Temozolomide significantly delays tumor growth and increases median survival in an orthotopic GBM mouse model, and (iv) mechanistically, β1 integrin/ JNK co-inhibition impaires HDAC function leading to elevated levels of euchromatin and enhancement of DNA double strand breaks, orchestrating G2/M phase arrest for radiochemosensitization downstream of ATM
Summary
Owing to the radiochemoresistant and infiltrative nature of Glioblastoma (GBM) [1,2,3,4], the prognosis of GBM patients is poor with an estimated five year overall survival of less than five percent [5, 6]. Several of the 8 beta and 18 alpha integrin subunits are overexpressed in GBM and a multitude of human malignancies, and are regarded as potential cancer targets owing to their role in tumor progression and metastasis [4, 26,27,28]. Β1 integrin and JNK are linked upon irradiation in an entity-dependent manner [33,34,35], but whether the crosstalk of adhesion and stress-related signaling is implicated in GBM adaptation, radioresistance and invasion has not been investigated. The presented study exploited the potential contextual synthetic lethal adaptation arising from β1 integrin and JNK cooperation by simultaneous inhibition of these two target molecules in GBM stem-like and patient-derived GBM cell cultures as well as GBM cell lines. The radiosensitization by β1 integrin/JNK co-inhibition was entailed by chromatin changes, enhanced DNA double strand breaks, associated ATM hyperphosphorylation and a prolonged G2/M cell cycle arrest
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