TY  - JOUR
A1  - Müller-Längle, Adriana
A1  - Lutz, Henrik
A1  - Hehlgans, Stephanie
A1  - Rödel, Franz
A1  - Rau, Kerstin
A1  - Laube, Bodo
T1  - NMDA receptor-mediated signaling pathways enhance radiation resistance, survival and migration in glioblastoma cells - a potential target for adjuvant radiotherapy
T2  - Cancers
N2  - 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.
KW  - ionotropic glutamate receptors
KW  - DNA repair
KW  - CREB inhibitor
KW  - NMDAR subunit GluN2B
KW  - radiotherapy
KW  - LN229
KW  - U-87MG
KW  - memantine
KW  - ifenprodil
KW  - sulfasalazine
Y1  - 2019
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/54333
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-543334
SN  - 2072-6694
N1  - 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
VL  - 11
IS  - 503
PB  - MDPI
CY  - Basel
ER  -