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

Müller-Längle Müller-Längle,Rau Rau,Hehlgans Hehlgans,Laube Laube,Rödel Rödel,Lutz Lutz

doi:10.3390/cancers11040503

Müller-Längle Müller-Längle, Rau Rau + Show 4 more

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https://doi.org/10.3390/cancers11040503

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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.

Highlights

Glioblastoma (WHO grade IV) is one of the most common and aggressive malignant primary brain tumor in humans [1]
We found in the glioblastoma cell lines LN229 and U-87MG that i) Glu improved DNA doubleresulted in a decreased cell migration, survival and a sensitization to ionizing radiation (IR)
To further analyze the impact of NMDAR-mediated cAMP-responsive element binding protein (CREB) activation on double-strand break (DSB) repair, we analyzed the relative levels of γH2AX in MK801 and KG-501 treated cells upon IR in the presence of Glu (Figure 4B). We found that both antagonists induced a significant increase in the amount of γH2AX protein after 30 min irradiation (Figure 4B), suggesting that an effective DNA repair of radiation-induced DSBs in LN229 cells may depend on both, the activation of NMDARs and CREB

Summary

Introduction

Glioblastoma (WHO grade IV) is one of the most common and aggressive malignant primary brain tumor in humans [1]. The so far limited success of the current multimodal therapy is likely due to the diffuse nature of the tumor and the prominent resistance to ionizing radiation (IR) with a high degree of recurrent invasive growth of the glioblastoma cells after the treatment [4,5,6,7]. In view of this and the outstanding role of RT for the prognosis of patients with glioblastoma, radiosensitizing substances addressing both, Cancers 2019, 11, 503; doi:10.3390/cancers11040503 www.mdpi.com/journal/cancers. With regard to a putative improvement of the efficacy of adjuvant RT, effects of the tumor microenvironment on glioma proliferation, invasion and survival should be considered [8]

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