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Glutamate in the Pathogenesis of Gliomas

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Handbook of Neurotoxicity

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Abstract

Recent studies have shown that glutamate may serve important roles in the pathobiology of primary brain tumors. Glutamate is produced and secreted from gliomas via specific glutamate transporters as a byproduct of glutathione synthesis. Glutamate also plays a major role in the phenotype of malignant gliomas by several mechanisms. The consequential interaction of glutamate with peritumoral neuronal glutamate receptors leads to the development of seizures and excitotoxicity. The latter is thought to promote the expansion gliomas in the vacated surrounding tissue. Glutaminergic receptors such as α-Amino-3-hydroxy-5-methyl-4-isoaxazolepropionic acid (AMPA) which lack the GluR2 subunit can activate the AKT and MAPK pathway, to promote the invasion of glioma cells into normal brain tissue. Stimulation of glutaminergic receptors also leads to the activation of focal adhesion kinase, which regulates the proliferation and motility of malignant glioma cells. Given the extensive involvement of glutamate in development of gliomas, it is likely that pharmacological therapies targeting glutaminergic receptors and glutamate transport may be useful to inhibit glutamate-mediated glioma growth.

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Abbreviations

AD:

Alzheimer’s disease

AEG-1:

Astrocyte elevated gene-1

AMPA:

α-Amino-3-hydroxy-5-methyl-4-isoaxazolepropionic acid

EGFR:

Epidermal growth factor receptor

GDH:

Glutamate dehydrogenase

GSH:

Glutathione

NMDA:

N-methyl-D-aspartate

p53:

Tumor suppressor protein

PDGFR:

Platelet derived growth factor receptor

PKC:

Protein kinase C

References

  • Albasanz, J. L., Ros, M., et al. (1997). Characterization of metabotropic glutamate receptors in rat C6 glioma cells. European Journal of Pharmacology, 326(1), 85–91.

    Article  CAS  Google Scholar 

  • Allritz, C., Bette, S., et al. (2010). Comparative structural and functional analysis of the GLT-1/EAAT-2 promoter from man and rat. Journal of Neuroscience Research, 88(6), 1234–1241.

    CAS  Google Scholar 

  • Arcella, A., Carpinelli, G., et al. (2005). Pharmacological blockade of group II metabotropic glutamate receptors reduces the growth of glioma cells in vivo. Neuro-Oncology, 7(3), 236–245.

    Article  CAS  Google Scholar 

  • Aronica, E., Gorter, J. A., et al. (2003). Expression and functional role of mGluR3 and mGluR5 in human astrocytes and glioma cells: Opposite regulation of glutamate transporter proteins. European Journal of Neuroscience, 17(10), 2106–2118.

    Article  Google Scholar 

  • Baumann, B. C., & Dorsey, J. F. (2011). Astrocyte-elevated gene-1 (AEG-1): Glioblastoma’s helping hand during times of hypoxia and glucose deprivation? Cancer Biology and Therapy, 11(1), 40–42.

    Article  CAS  Google Scholar 

  • Calabrese, C., Poppleton, H., et al. (2007). A perivascular niche for brain tumor stem cells. Cancer Cell, 11(1), 69–82.

    Article  CAS  Google Scholar 

  • Caruso, A., Ciccarelli, R., et al. (1997). Opposite influence of the metabotropic glutamate receptor subtypes mGlu3 and -5 on astrocyte proliferation in culture. Journal of Neurochemistry, 69, S234–S234.

    Google Scholar 

  • Chretien, F., Vallat-Decouvelaere, A. V., et al. (2002). Expression of excitatory amino acid transporter-2 (EAAT-2) and glutamine synthetase (GS) in brain macrophages and microglia of SIVmac251-infected macaques. Neuropathology and Applied Neurobiology, 28(5), 410–417.

    Article  CAS  Google Scholar 

  • Chung, W. J., Lyons, S. A., et al. (2005). Inhibition of cystine uptake disrupts the growth of primary brain tumors. Journal of Neuroscience, 25(31), 7101–7110.

    Article  CAS  Google Scholar 

  • Colman, H., Zhang, L., et al. (2010). A multigene predictor of outcome in glioblastoma. Neuro-Oncology, 12(1), 49–57.

    Article  CAS  Google Scholar 

  • Condorelli, D. F., DellAlbani, P., et al. (1997). Metabotropic glutamate receptor expression in cultured rat astrocytes and human gliomas. Neurochemical Research, 22(9), 1127–1133.

    Article  CAS  Google Scholar 

  • Courtney, M. J., Lambert, J. J., et al. (1990). The interactions between plasma-membrane depolarization and glutamate receptor activation in the regulation of cytoplasmic free calcium in cultured cerebellar granule cells. Journal of Neuroscience, 10(12), 3873–3879.

    Article  CAS  Google Scholar 

  • de Groot, J. F., Liu, T. J., et al. (2005). The excitatory amino acid transporter-2 induces apoptosis and decreases glioma growth in vitro and in vivo. Cancer Research, 65(5), 1934–1940.

    Article  Google Scholar 

  • Ekici, M., Keim, A., et al. (2012). Chromatin structure and expression of the AMPA receptor subunit Glur2 in human glioma cells: Major regulatory role of REST and Sp1. Journal of Cellular Biochemistry, 113(2), 528–543.

    Article  CAS  Google Scholar 

  • Frandsen, A., Drejer, J., et al. (1989). Direct evidence that excitotoxicity in cultured neurons is mediated via N-methyl-D-aspartate (NMDA) as well as non-NMDA receptors. Journal of Neurochemistry, 53(1), 297–299.

    Article  CAS  Google Scholar 

  • Fuchs, S. A., Peeters-Scholte, C. M., et al. (2012). Increased concentrations of both NMDA receptor co-agonists D-serine and glycine in global ischemia: A potential novel treatment target for perinatal asphyxia. Amino Acids, 43(1), 355–363.

    Article  CAS  Google Scholar 

  • Grossman, S. A., Ye, X. B., et al. (2009). Talampanel with standard radiation and temozolomide in patients with newly diagnosed glioblastoma: A multicenter phase II trial. Journal of Clinical Oncology, 27(25), 4155–4161.

    Article  CAS  Google Scholar 

  • Hu, G., Wei, Y., et al. (2009). The multifaceted role of MTDH/AEG-1 in cancer progression. Clinical Cancer Research, 15(18), 5615–5620.

    Article  CAS  Google Scholar 

  • Ishiuchi, S., Yoshida, Y., et al. (2007). Ca2+−permeable AMPA receptors regulate growth of human glioblastoma via Akt activation. The Journal of Neuroscience, 27(30), 7987–8001.

    Article  CAS  Google Scholar 

  • Iwamoto, F. M., Kreisl, T. N., et al. (2010). Phase 2 trial of talampanel, a glutamate receptor inhibitor, for adults with recurrent malignant gliomas. Cancer, 116(7), 1776–1782.

    Article  CAS  Google Scholar 

  • Kandil, S., Brennan, L., et al. (2010). Glutathione depletion causes a JNK and p38(MAPK)-mediated increase in expression of cystathionine-gamma-lyase and upregulation of the transsulfuration pathway in C6 glioma cells. Neurochemistry International, 56(4), 611–619.

    Article  CAS  Google Scholar 

  • Kang, D. C., Su, Z. Z., et al. (2005). Cloning and characterization of HIV-1-inducible astrocyte elevated gene-1, AEG-1. Gene, 353(1), 8–15.

    Article  CAS  Google Scholar 

  • Kim, J. Y., Kanai, Y., et al. (2001). Human cystine/glutamate transporter: cDNA cloning and upregulation by oxidative stress in glioma cells. Biochimica et Biophysica Acta, 1512(2), 335–344.

    Article  CAS  Google Scholar 

  • Kim, D. S., Na, D. G., et al. (2009). Distinguishing tumefactive demyelinating lesions from glioma or central nervous system lymphoma: Added value of unenhanced CT compared with conventional contrast-enhanced MR imaging. Radiology, 251(2), 467–475.

    Article  Google Scholar 

  • Kimelberg, H. K., & Kettenmann, H. (1990). Swelling-induced changes in electrophysiological properties of cultured astrocytes and oligodendrocytes.1. Effects on membrane-potentials, input impedance and cell-cell coupling. Brain Research, 529(1–2), 255–261.

    Article  CAS  Google Scholar 

  • Kimelberg, H. K., Goderie, S., et al. (1990a). Swelling-induced membrane-transport changes in astrocytes. Advances in Neural Regeneration Research, 60, 199–214.

    Google Scholar 

  • Kimelberg, H. K., Goderie, S. K., et al. (1990b). Volume changes of astrocytes Invitro as a model for pathological astrocytic swelling. Differentiation and Functions of Glial Cells, 55, 335–348.

    Google Scholar 

  • Kimelberg, H. K., Goderie, S. K., et al. (1990c). Swelling-induced release of glutamate, aspartate, and taurine from astrocyte cultures. Journal of Neuroscience, 10(5), 1583–1591.

    Article  CAS  Google Scholar 

  • Lalo, U., Pankratov, Y., et al. (2011). Ionotropic receptors in neuronal-astroglial signalling: What is the role of “excitable” molecules in non-excitable cells. Biochimica et Biophysica Acta, 1813(5), 992–1002.

    Article  CAS  Google Scholar 

  • Lee, M. C., Ting, K. K., et al. (2010). Characterisation of the expression of NMDA receptors in human astrocytes. PLoS One, 5(11).

    Google Scholar 

  • Lee, S. G., Kim, K., et al. (2011). Oncogene AEG-1 promotes glioma-induced neurodegeneration by increasing glutamate excitotoxicity. Cancer Research, 71(20), 6514–6523.

    Article  CAS  Google Scholar 

  • Lipton, S. A. (2004). Paradigm shift in NMDA receptor antagonist drug development: Molecular mechanism of uncompetitive inhibition by memantine in the treatment of Alzheimer’s disease and other neurologic disorders. Journal of Alzheimers Disease, 6(6), S61–S74.

    CAS  Google Scholar 

  • Liu, Q. Y., Schaffner, A. E., et al. (1997). Astrocytes regulate amino acid receptor current densities in embryonic rat hippocampal neurons. Journal of Neurobiology, 33(6), 848–864.

    Article  CAS  Google Scholar 

  • Lyons, S. A., Chung, W. J., et al. (2007). Autocrine glutamate signaling promotes glioma cell invasion. Cancer Research, 67(19), 9463–9471.

    Article  CAS  Google Scholar 

  • Mattson, M. P., Wang, H., et al. (1991). Developmental expression, compartmentalization, and possible role in excitotoxicity of a putative NMDA receptor protein in cultured hippocampal neurons. Brain Research, 565(1), 94–108.

    Article  CAS  Google Scholar 

  • Montana, V., Malarkey, E. B., et al. (2006). Vesicular transmitter release from astrocytes. Glia, 54(7), 700–715.

    Article  Google Scholar 

  • Moots, P. L., Maciunas, R. J., et al. (1995). The course of seizure disorders in patients with malignant gliomas. Archives of Neurology, 52(7), 717–724.

    Article  CAS  Google Scholar 

  • Noch, E., & Khalili, K. (2009). Molecular mechanisms of necrosis in glioblastoma: The role of glutamate excitotoxicity. Cancer Biology & Therapy, 8(19), 1791–1797.

    Article  CAS  Google Scholar 

  • Noch, E., Bookland, M., et al. (2011). Astrocyte-elevated gene-1 (AEG-1) induction by hypoxia and glucose deprivation in glioblastoma. Cancer Biology & Therapy, 11(1), 32–39.

    Article  CAS  Google Scholar 

  • Ohgaki, H., & Kleihues, P. (2009). Genetic alterations and signaling pathways in the evolution of gliomas. Cancer Science, 100(12), 2235–2241.

    Article  CAS  Google Scholar 

  • Oka, A., Belliveau, M. J., et al. (1993). Vulnerability of oligodendroglia to glutamate – pharmacology, mechanisms, and prevention. Journal of Neuroscience, 13(4), 1441–1453.

    Article  CAS  Google Scholar 

  • Ortinski, P. I., Dong, J. H., et al. (2010). Selective induction of astrocytic gliosis generates deficits in neuronal inhibition. Nature Neuroscience, 13(5), 584–U593.

    Article  CAS  Google Scholar 

  • Patel, S. A., Warren, B. A., et al. (2004). Differentiation of substrate and non-substrate inhibitors of transport system x(c)(-): An obligate exchanger of L-glutamate and L-cystine. Neuropharmacology, 46(2), 273–284.

    Article  CAS  Google Scholar 

  • Piao, Y. J., Lu, L., et al. (2009). AMPA receptors promote perivascular glioma invasion via beta 1 integrin-dependent adhesion to the extracellular matrix. Neuro-Oncology, 11(3), 260–273.

    Article  CAS  Google Scholar 

  • Ponzio, T. A., Ni, Y., et al. (2006). Vesicular glutamate transporter expression in supraoptic neurones suggests a glutamatergic phenotype. Journal of Neuroendocrinology, 18(4), 253–265.

    Article  CAS  Google Scholar 

  • Robe, P. A., Bentires-Alj, M., et al. (2004). In vitro and in vivo activity of the nuclear factor-kappa B inhibitor sulfasalazine in human glioblastomas. Clinical Cancer Research, 10(16), 5595–5603.

    Article  CAS  Google Scholar 

  • Rzeski, W., Turski, L., et al. (2001). Glutamate antagonists limit tumor growth. Proceedings of the National Academy of Sciences of the United States of America, 98(11), 6372–6377.

    Article  CAS  Google Scholar 

  • Sato, H., Tamba, M., et al. (1999). Cloning and expression of a plasma membrane cystine/glutamate exchange transporter composed of two distinct proteins. Journal of Biological Chemistry, 274(17), 11455–11458.

    Article  CAS  Google Scholar 

  • Savaskan, N. E., Seufert, S., et al. (2011). Dissection of mitogenic and neurodegenerative actions of cystine and glutamate in malignant gliomas. Oncogene, 30(1), 43–53.

    Article  CAS  Google Scholar 

  • Simon, M., & von Lehe, M. (2011). Glioma-related seizures: Glutamate is the key. Nature Medicine, 17(10), 1190–1191.

    Article  CAS  Google Scholar 

  • Singh, J., & Kaur, G. (2009). Transcriptional regulation of PSA-NCAM expression by NMDA receptor activation in RA-differentiated C6 glioma cultures. Brain Research Bulletin, 79(3–4), 157–168.

    Article  CAS  Google Scholar 

  • Stepulak, A., Luksch, H., et al. (2009). Expression of glutamate receptor subunits in human cancers. Histochemistry and Cell Biology, 132(4), 435–445.

    Article  CAS  Google Scholar 

  • Unger, T., Lakowa, N., et al. (2012). Transcriptional regulation of the GLAST/EAAT-1 gene in rat and man. Cellular and Molecular Neurobiology, 32(4), 539–547.

    Article  CAS  Google Scholar 

  • Weber, M., Dietrich, D., et al. (2001). 6-Hydroxykynurenic acid and kynurenic acid differently antagonise AMPA and NMDA receptors in hippocampal neurones. Journal of Neurochemistry, 77(4), 1108–1115.

    Article  CAS  Google Scholar 

  • Yang, C. D., Sudderth, J., et al. (2009). Glioblastoma cells require glutamate dehydrogenase to survive impairments of glucose metabolism or Akt signaling. Cancer Research, 69(20), 7986–7993.

    Article  CAS  Google Scholar 

  • Ye, Z. C., & Ransom, B. R. (2003). Potential involvement of hemichannels in ATP-stimulated glutamate release from cultured and astrocytes. Glia, 32–32.

    Google Scholar 

  • Ye, Z. C., & Sontheimer, H. (1999a). Glioma cells release excitotoxic concentrations of glutamate. Cancer Research, 59(17), 4383–4391.

    CAS  Google Scholar 

  • Ye, Z. C., & Sontheimer, H. (1999b). Metabotropic glutamate receptor agonists reduce glutamate release from cultured astrocytes. Glia, 25(3), 270–281.

    Article  CAS  Google Scholar 

  • Ye, Z. C., Rothstein, J. D., et al. (1999). Compromised glutamate transport in human glioma cells: Reduction-mislocalization of sodium-dependent glutamate transporters and enhanced activity of cystine-glutamate exchange. Journal of Neuroscience, 19(24), 10767–10777.

    Article  CAS  Google Scholar 

  • Ye, Z. C., Wyeth, M. S., et al. (2003). Functional hemichannels in astrocytes: A novel mechanism of glutamate release. Journal of Neuroscience, 23(9), 3588–3596.

    Article  CAS  Google Scholar 

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Acknowledgments

This work was supported by the NHMRC Capacity Building Grant to Prof Perminder Sachdev. Nady Braidy is the recipient of an Alzheimer’s Australia Viertel Foundation Postdoctoral Research Fellowship at the University of New South Wales. We sincerely thank the Rebecca Cooper Medical Research Foundation for ongoing financial support of our research.

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Authors and Affiliations

  1. Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia

    Nady Braidy

  2. Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia

    Tharusha Jayasena & Perminder Sachdev

  3. School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia

    Anne Poljak & Seray Adams

  4. Bioanalytical Mass Spectrometry Facility, University of New South Wales, Sydney, NSW, Australia

    Anne Poljak

  5. Neuropsychiatric Institute, Prince of Wales Hospital, Sydney, NSW, Australia

    Perminder Sachdev

  6. Neuropharmacology Group, MND and Neurodegenerative Diseases Research Centre, Macquarie University, Sydney, NSW, Australia

    Anne Poljak

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  1. Nady Braidy
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Correspondence to Nady Braidy .

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Editors and Affiliations

  1. Department of Biomedical Sciences, Quillen College of Medicine East Tennessee State University, Johnson City, TN, USA

    Richard M. Kostrzewa

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Braidy, N., Poljak, A., Jayasena, T., Adams, S., Sachdev, P. (2022). Glutamate in the Pathogenesis of Gliomas. In: Kostrzewa, R.M. (eds) Handbook of Neurotoxicity. Springer, Cham. https://doi.org/10.1007/978-3-031-15080-7_149

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