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Cancers 2019, 11(3), 306; https://doi.org/10.3390/cancers11030306

NMDA Receptor Signaling Mediates cFos Expression via Top2β-Induced DSBs in Glioblastoma Cells

Neurophysiology and Neurosensory Systems, Technische Universität Darmstadt, Schnittspahnstrasse 3, 64287 Darmstadt, Germany
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Received: 18 January 2019 / Revised: 20 February 2019 / Accepted: 27 February 2019 / Published: 5 March 2019
(This article belongs to the Special Issue Ion Channels in Cancer)
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Abstract

The activation of Ca2+-permeable N-methyl-D-aspartic acid (NMDA) receptor channels (NMDARs) is crucial for the development and survival of neurons, but many cancers use NMDAR-mediated signaling as well, enhancing the growth and invasiveness of tumors. Thus, NMDAR-dependent pathways emerge as a promising target in cancer therapy. Here, we use the LN229 and U-87MG glioblastoma multiforme (GBM) cells and immunofluorescence staining of 53BP1 to analyze NMDAR-induced DNA double-strand breaks (DSBs), which represent an important step in the NMDAR signaling pathway in neurons by facilitating the expression of early response genes. Our results show that NMDAR activation leads to the induction of DSBs in a subpopulation of glioma cells. In a further analogy to neurons, our results demonstrate that the induction of DSBs in LN229 cells is dependent on the activity of topoisomerase IIβ (Top2β). Western blot analysis revealed that the inhibition of NMDARs, cAMP-responsive element binding transcription factor (CREB) and Top2β decreased the expression of the proto-oncogene cFos. Knockdown of Top2β with siRNAs resulted in a downregulation of cFos and increased the radiosensitivity of LN229 cells in clonogenic survival. We also observed impaired cFos expression upon NMDAR and Top2β inhibition in a primary GBM cell line, suggesting that NMDAR signaling may be widely used by GBMs, demonstrating the potential of targeting NMDAR signaling proteins for GBM therapy. View Full-Text
Keywords: GBM; ionotropic glutamate receptor; topoisomerase IIβ; stimulus induced DSB; early response gene; NMDAR subunit GluN2B; radiotherapy; LN229; U-87MG; ifenprodil GBM; ionotropic glutamate receptor; topoisomerase IIβ; stimulus induced DSB; early response gene; NMDAR subunit GluN2B; radiotherapy; LN229; U-87MG; ifenprodil
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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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Lutz, H.; Nguyen, T.A.; Joswig, J.; Rau, K.; Laube, B. NMDA Receptor Signaling Mediates cFos Expression via Top2β-Induced DSBs in Glioblastoma Cells. Cancers 2019, 11, 306.

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