NMDA receptor-mediated signaling pathways enhance radiation resistance, survival and migration in glioblastoma cells - a potential target for adjuvant radiotherapy

  • Glioblastoma is one of the most aggressive malignant brain tumors, with a survival time less than 15 months and characterized by a high radioresistance and the property of infiltrating the brain. Recent data indicate that the malignancy of glioblastomas depends on glutamatergic signaling via ionotropic glutamate receptors. In this study we revealed functional expression of Ca2+-permeable NMDARs in three glioblastoma cell lines. Therefore, we investigated the impact of this receptor on cell survival, migration and DNA double-strand break (DSB) repair in the presence of both, glutamate and NMDAR antagonists, and after clinically relevant doses of ionizing radiation. Our results indicate that treatment with NMDAR antagonists slowed the growth and migration of glutamate-releasing LN229 cells, suggesting that activation of NMDARs facilitate tumor expansion. Furthermore, we found that DSB-repair upon radiation was more effective in the presence of glutamate. In contrast, antagonizing the NMDAR or the Ca2+-dependent transcription factor CREB impaired DSB-repair similarly and resulted in a radiosensitizing effect in LN229 and U-87MG cells, indicating a common link between NMDAR signaling and CREB activity in glioblastoma. Since the FDA-approved NMDAR antagonists memantine and ifenprodil showed differential radiosensitizing effects, these compounds may constitute novel optimizations for therapeutic interventions in glioblastoma.

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Author:Adriana Müller-Längle, Henrik Lutz, Stephanie HehlgansORCiDGND, Franz RödelORCiDGND, Kerstin Rau, Bodo LaubeORCiDGND
Parent Title (English):Cancers
Place of publication:Basel
Document Type:Article
Date of Publication (online):2019/04/09
Date of first Publication:2019/04/09
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/05/11
Tag:CREB inhibitor; DNA repair; LN229; NMDAR subunit GluN2B; U-87MG; ifenprodil; ionotropic glutamate receptors; memantine; radiotherapy; sulfasalazine
Page Number:16
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0