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Cancers 2019, 11(4), 503; https://doi.org/10.3390/cancers11040503

NMDA Receptor-Mediated Signaling Pathways Enhance Radiation Resistance, Survival and Migration in Glioblastoma Cells—A Potential Target for Adjuvant Radiotherapy

1
Neurophysiology and Neurosensory Systems, Technische Universität Darmstadt, Schnittspahnstrasse 3, 64287 Darmstadt, Germany
2
Department of Radiotherapy and Oncology, Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
*
Author to whom correspondence should be addressed.
Received: 29 December 2018 / Revised: 22 March 2019 / Accepted: 4 April 2019 / Published: 9 April 2019
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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Abstract

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.
Keywords: ionotropic glutamate receptors; DNA repair; CREB inhibitor; NMDAR subunit GluN2B; radiotherapy; LN229; U-87MG; memantine; ifenprodil; sulfasalazine ionotropic glutamate receptors; DNA repair; CREB inhibitor; NMDAR subunit GluN2B; radiotherapy; LN229; U-87MG; memantine; ifenprodil; sulfasalazine
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 (CC BY 4.0).
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Müller-Längle, A.; Lutz, H.; Hehlgans, S.; Rödel, F.; Rau, K.; Laube, B. NMDA Receptor-Mediated Signaling Pathways Enhance Radiation Resistance, Survival and Migration in Glioblastoma Cells—A Potential Target for Adjuvant Radiotherapy. Cancers 2019, 11, 503.

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