Abstract
Malignant glioma represents one of the most aggressive and lethal human neoplasias. A hallmark of gliomas is their rapid proliferation and destruction of vital brain tissue, a process in which excessive glutamate release by glioma cells takes center stage. Pharmacologic antagonism with glutamate signaling through ionotropic glutamate receptors attenuates glioma progression in vivo, indicating that glutamate release by glioma cells is a prerequisite for rapid glioma growth. Glutamate has been suggested to promote glioma cell proliferation in an autocrine or paracrine manner, in particular by activation of the (RS)-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrate (AMPA) subtype of glutamate receptors. Here, we dissect the effects of glutamate secretion on glioma progression. Glioma cells release glutamate through the amino-acid antiporter system Xc−, a process that is mechanistically linked with cystine incorporation. We show that disrupting glutamate secretion by interfering with the system Xc− activity attenuates glioma cell proliferation solely cystine dependently, whereas glutamate itself does not augment glioma cell growth in vitro. Neither AMPA receptor agonism nor antagonism affects glioma growth in vitro. On a molecular level, AMPA insensitivity is concordant with a pronounced transcriptional downregulation of AMPA receptor subunits or overexpression of the fully edited GluR2 subunit, both of which block receptor activity. Strikingly, AMPA receptor inhibition in tumor-implanted brain slices resulted in markedly reduced tumor progression associated with alleviated neuronal cell death, suggesting that the ability of glutamate to promote glioma progression strictly requires the tumor microenvironment. Concerning a potential pharmacotherapy, targeting system Xc− activity disrupts two major pathophysiological properties of glioma cells, that is, the induction of excitotoxic neuronal cell death and incorporation of cystine required for rapid proliferation.
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Change history
22 February 2023
A Correction to this paper has been published: https://doi.org/10.1038/s41388-023-02634-5
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Acknowledgements
We thank Nadine Scheufler and Philip Rummel (both Erlangen) for experimental support. Jan Csupor (Berlin) is acknowledged for technical assistance. This study was supported by the ‘Wilhelm Sander-Stiftung’ (to EH), the ‘Institut Danone’ (to NES, IYE and EH), the ‘International Human Frontiers Science Program’ (to NES), the ‘ELAN-Programm’ (to IYE), the ‘Köln Fortune Programm’ (to EH) and the ‘Center for Molecular Medicine Cologne (CMMC)’ (to EH).
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Savaskan, N., Seufert, S., Hauke, J. et al. Dissection of mitogenic and neurodegenerative actions of cystine and glutamate in malignant gliomas. Oncogene 30, 43–53 (2011). https://doi.org/10.1038/onc.2010.391
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DOI: https://doi.org/10.1038/onc.2010.391
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