Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Dissection of mitogenic and neurodegenerative actions of cystine and glutamate in malignant gliomas

Oncogene volume 30, pages 43–53 (2011)Cite this article

Subjects

A Correction to this article was published on 22 February 2023

This article has been updated

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

Change history

References

  • Behrens PF, Langemann H, Strohschein R, Draeger J, Hennig J . (2000). Extracellular glutamate and other metabolites in and around RG2 rat glioma: an intracerebral microdialysis study. J Neurooncol 47: 11–22.

    Article  CAS  PubMed  Google Scholar 

  • Brusa R, Zimmermann F, Koh DS, Feldmeyer D, Gass P, Seeburg PH et al. (1995). Early-onset epilepsy and postnatal lethality associated with an editing-deficient GluR-B allele in mice. Science 270: 1677–1680.

    Article  CAS  PubMed  Google Scholar 

  • Chung WJ, Lyons SA, Nelson GM, Hamza H, Gladson CL, Gillespie GY et al. (2005). Inhibition of cystine uptake disrupts the growth of primary brain tumors. J Neurosci 25: 7101–7110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chung WJ, Sontheimer H . (2009). Sulfasalazine inhibits the growth of primary brain tumors independent of nuclear factor-kappaB. J Neurochem 110: 182–193.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • de Groot JF, Piao Y, Lu L, Fuller GN, Yung WK . (2008). Knockdown of GluR1 expression by RNA interference inhibits glioma proliferation. J Neurooncol 88: 121–133.

    Article  CAS  PubMed  Google Scholar 

  • DeAngelis LM . (2001). Brain tumors. N Engl J Med 344: 114–123.

    Article  CAS  PubMed  Google Scholar 

  • Donevan SD, Rogawski MA . (1993). GYKI 52466, a 2,3-benzodiazepine, is a highly selective, noncompetitive antagonist of AMPA/kainate receptor responses. Neuron 10: 51–59.

    Article  CAS  PubMed  Google Scholar 

  • Eyupoglu IY, Hahnen E, Buslei R, Siebzehnrubl FA, Savaskan NE, Luders M et al. (2005a). Suberoylanilide hydroxamic acid (SAHA) has potent anti-glioma properties in vitro, ex vivo and in vivo. J Neurochem 93: 992–999.

    Article  PubMed  Google Scholar 

  • Eyupoglu IY, Hahnen E, Heckel A, Siebzehnrubl FA, Buslei R, Fahlbusch R et al. (2005b). Malignant glioma-induced neuronal cell death in an organotypic glioma invasion model. Technical note. J Neurosurg 102: 738–744.

    Article  PubMed  Google Scholar 

  • Eyupoglu IY, Hahnen E, Trankle C, Savaskan NE, Siebzehnrubl FA, Buslei R et al. (2006). Experimental therapy of malignant gliomas using the inhibitor of histone deacetylase MS-275. Mol Cancer Ther 5: 1248–1255.

    Article  PubMed  Google Scholar 

  • Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A et al. (2007). Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev 21: 2683–2710.

    Article  CAS  PubMed  Google Scholar 

  • Huang Y, Dai Z, Barbacioru C, Sadee W . (2005). Cystine-glutamate transporter SLC7A11 in cancer chemosensitivity and chemoresistance. Cancer Res 65: 7446–7454.

    Article  CAS  PubMed  Google Scholar 

  • Ishiuchi S, Tsuzuki K, Yoshida Y, Yamada N, Hagimura N, Okado H et al. (2002). Blockage of Ca(2+)-permeable AMPA receptors suppresses migration and induces apoptosis in human glioblastoma cells. Nat Med 8: 971–978.

    Article  CAS  PubMed  Google Scholar 

  • Jones DP, Go YM, Anderson CL, Ziegler TR, Kinkade Jr JM, Kirlin WG . (2004). Cysteine/cystine couple is a newly recognized node in the circuitry for biologic redox signaling and control. FASEB J 18: 1246–1248.

    Article  CAS  PubMed  Google Scholar 

  • Liu RR, Brown CE, Murphy TH . (2007). Differential regulation of cell proliferation in neurogenic zones in mice lacking cystine transport by xCT. Biochem Biophys Res Commun 364: 528–533.

    Article  CAS  PubMed  Google Scholar 

  • Lomeli H, Mosbacher J, Melcher T, Hoger T, Geiger JR, Kuner T et al. (1994). Control of kinetic properties of AMPA receptor channels by nuclear RNA editing. Science 266: 1709–1713.

    Article  CAS  PubMed  Google Scholar 

  • Lu W, Shi Y, Jackson AC, Bjorgan K, During MJ, Sprengel R et al. (2009). Subunit composition of synaptic AMPA receptors revealed by a single-cell genetic approach. Neuron 62: 254–268.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lyons SA, Chung WJ, Weaver AK, Ogunrinu T, Sontheimer H . (2007). Autocrine glutamate signaling promotes glioma cell invasion. Cancer Res 67: 9463–9471.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maas S, Patt S, Schrey M, Rich A . (2001). Underediting of glutamate receptor GluR-B mRNA in malignant gliomas. Proc Natl Acad Sci USA 98: 14687–14692.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marcus HJ, Carpenter KL, Price SJ, Hutchinson PJ . (2010). In vivo assessment of high-grade glioma biochemistry using microdialysis: a study of energy-related molecules, growth factors and cytokines. J Neurooncol 97: 11–23.

    Article  CAS  PubMed  Google Scholar 

  • Mawatari K, Yasui Y, Sugitani K, Takadera T, Kato S . (1996). Reactive oxygen species involved in the glutamate toxicity of C6 glioma cells via xc antiporter system. Neuroscience 73: 201–208.

    Article  CAS  PubMed  Google Scholar 

  • Mosbacher J, Schoepfer R, Monyer H, Burnashev N, Seeburg PH, Ruppersberg JP . (1994). A molecular determinant for submillisecond desensitization in glutamate receptors. Science 266: 1059–1062.

    Article  CAS  PubMed  Google Scholar 

  • Ohgaki H, Kleihues P . (2005). Epidemiology and etiology of gliomas. Acta Neuropathol (Berl) 109: 93–108.

    Article  Google Scholar 

  • Patel SA, Warren BA, Rhoderick JF, Bridges RJ . (2004). Differentiation of substrate and non-substrate inhibitors of transport system xc(–): an obligate exchanger of L-glutamate and L-cystine. Neuropharmacology 46: 273–284.

    Article  CAS  PubMed  Google Scholar 

  • Pham AN, Blower PE, Alvarado O, Ravula R, Gout PW, Huang Y . (2010). Pharmacogenomic approach reveals a role for the x(c)– cystine/glutamate antiporter in growth and celastrol resistance of glioma cell lines. J Pharmacol Exp Ther 332: 949–958.

    Article  CAS  PubMed  Google Scholar 

  • Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D et al. (2004). ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia 6: 1–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robe PA, Martin DH, Nguyen-Khac MT, Artesi M, Deprez M, Albert A et al. (2009). Early termination of ISRCTN45828668, a phase 1/2 prospective, randomized study of sulfasalazine for the treatment of progressing malignant gliomas in adults. BMC Cancer 9: 372.

    Article  PubMed  PubMed Central  Google Scholar 

  • Sato H, Shiiya A, Kimata M, Maebara K, Tamba M, Sakakura Y et al. (2005). Redox imbalance in cystine/glutamate transporter-deficient mice. J Biol Chem 280: 37423–37429.

    Article  CAS  PubMed  Google Scholar 

  • Savaskan NE, Hahnen E, Eyupoglu IY . (2009). The x(c)(–) cystine/glutamate antiporter (xCT) as a potential target for therapy of cancer: yet another cytotoxic anticancer approach? J Cell Physiol 220: 531–532; author reply 533–534.

    Article  CAS  PubMed  Google Scholar 

  • Savaskan NE, Heckel A, Hahnen E, Engelhorn T, Doerfler A, Ganslandt O et al. (2008). Small interfering RNA-mediated xCT silencing in gliomas inhibits neurodegeneration and alleviates brain edema. Nat Med 14: 629–632.

    Article  CAS  PubMed  Google Scholar 

  • Savaskan NE, Rocha L, Kotter MR, Baer A, Lubec G, van Meeteren LA et al. (2007). Autotaxin (NPP-2) in the brain: cell type-specific expression and regulation during development and after neurotrauma. Cell Mol Life Sci 64: 230–243.

    Article  CAS  PubMed  Google Scholar 

  • Schwenk J, Harmel N, Zolles G, Bildl W, Kulik A, Heimrich B et al. (2009). Functional proteomics identify cornichon proteins as auxiliary subunits of AMPA receptors. Science 323: 1313–1319.

    Article  CAS  PubMed  Google Scholar 

  • Shih AY, Erb H, Sun X, Toda S, Kalivas PW, Murphy TH . (2006). Cystine/glutamate exchange modulates glutathione supply for neuroprotection from oxidative stress and cell proliferation. J Neurosci 26: 10514–10523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun L, Hui AM, Su Q, Vortmeyer A, Kotliarov Y, Pastorino S et al. (2006). Neuronal and glioma-derived stem cell factor induces angiogenesis within the brain. Cancer Cell 9: 287–300.

    Article  CAS  PubMed  Google Scholar 

  • Takano T, Lin JH, Arcuino G, Gao Q, Yang J, Nedergaard M . (2001). Glutamate release promotes growth of malignant gliomas. Nat Med 7: 1010–1015.

    Article  CAS  PubMed  Google Scholar 

  • Turski L, Huth A, Sheardown M, McDonald F, Neuhaus R, Schneider HH et al. (1998). ZK200775: a phosphonate quinoxalinedione AMPA antagonist for neuroprotection in stroke and trauma. Proc Natl Acad Sci USA 95: 10960–10965.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van Vuurden DG, Yazdani M, Bosma I, Broekhuizen AJ, Postma TJ, Heimans JJ et al. (2009). Attenuated AMPA receptor expression allows glioblastoma cell survival in glutamate-rich environment. PLoS One 4: e5953.

    Article  PubMed  PubMed Central  Google Scholar 

  • Vanhoutte N, Abarca-Quinones J, Jordan BF, Gallez B, Maloteaux JM, Hermans E . (2009). Enhanced expression of the high affinity glutamate transporter GLT-1 in C6 glioma cells delays tumour progression in rat. Exp Neurol 218: 56–63.

    Article  CAS  PubMed  Google Scholar 

  • Ye ZC, Rothstein JD, Sontheimer H . (1999). Compromised glutamate transport in human glioma cells: reduction-mislocalization of sodium-dependent glutamate transporters and enhanced activity of cystine-glutamate exchange. J Neurosci 19: 10767–10777.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ye ZC, Sontheimer H . (1999). Glioma cells release excitotoxic concentrations of glutamate. Cancer Res 59: 4383–4391.

    CAS  PubMed  Google Scholar 

  • Yoshida Y, Tsuzuki K, Ishiuchi S, Ozawa S . (2006). Serum-dependence of AMPA receptor-mediated proliferation in glioma cells. Pathol Int 56: 262–271.

    Article  CAS  PubMed  Google Scholar 

  • Zhuge J, Cederbaum AI . (2006). Serum deprivation-induced HepG2 cell death is potentiated by CYP2E1. Free Radic Biol Med 40: 63–74.

    Article  CAS  PubMed  Google Scholar 

Download references

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).

Author information

Author notes

  1. N E Savaskan and S Seufert: These authors contributed equally as first authors.

  2. I Y Eyüpoglu and E Hahnen: These authors contributed equally as senior authors.

Authors and Affiliations

  1. Institute of Cell Biology and Neurobiology, Charité-Universitätsmedizin Berlin, Berlin, Germany

    N E Savaskan

  2. Institute of Human Genetics, University of Cologne, Cologne, Germany

    S Seufert, J Hauke & E Hahnen

  3. Institute of Genetics, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany

    S Seufert, J Hauke & E Hahnen

  4. Department of Pharmacology and Toxicology, Institute of Pharmacy, University of Bonn, Bonn, Germany

    C Tränkle

  5. Department of Neurosurgery, University of Erlangen-Nuremberg, Erlangen, Germany

    I Y Eyüpoglu

  6. Institute of Neuropathology, University Hospital Erlangen, Erlangen, Germany

    E Hahnen

Authors
  1. N E Savaskan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Seufert
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Hauke
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C Tränkle
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. I Y Eyüpoglu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E Hahnen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to N E Savaskan or E Hahnen.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2010.391

Keywords

This article is cited by

Search

Advanced search

Quick links