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.

  • Article
  • Published:

Blockage of Ca2+-permeable AMPA receptors suppresses migration and induces apoptosis in human glioblastoma cells

Nature Medicine volume 8, pages 971–978 (2002)Cite this article

Abstract

Glioblastoma multiforme is the most undifferentiated type of brain tumor, and its prognosis is extremely poor. Glioblastoma cells exhibit highly migratory and invasive behavior, which makes surgical intervention unsuccessful. Here, we showed that glioblastoma cells express Ca2+-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-type glutamate receptors assembled from the GluR1 and/or GluR4 subunits, and that their conversion to Ca2+-impermeable receptors by adenovirus-mediated transfer of the GluR2 cDNA inhibited cell locomotion and induced apoptosis. In contrast, overexpression of Ca2+-permeable AMPA receptors facilitated migration and proliferation of the tumor cells. These findings indicate that Ca2+-permeable AMPA receptors have crucial roles in growth of glioblastoma. Blockage of these Ca2+-permeable receptors may be a useful therapeutic strategy for the prevention of glioblastoma invasion.

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: AMPA receptors expressed in human glioblastoma cells.
Figure 2: AMPA-induced changes in [Ca2+]i in cultured tumor cells.
Figure 3: Effects of adenoviral-mediated expression of AMPA receptor subunits.
Figure 4: Effects of expression of GluR2 and GluR2(Q) on cell migration.
Figure 5: Effects of GluR2 expression on tumor transplantation.
Figure 6: Effects of manipulation of AMPA receptors on tumor growth.

Similar content being viewed by others

References

  1. Kleihues, P. et al. Glioblastoma. World Health Organization Classsification of Tumours. in Pathology and Genetics of Tumours of the Nervous Systems (eds. Kleihues, P. & Cavenee, W.K.) 29–39 (IARC Press, Lyon, France, 2000).

    Google Scholar 

  2. Blakemore, W.F., Franklin R.J.M. & Noble, M. Glial cell transplantation and the repair of demyelinating lesions. In Glial Cell Development (ed. Jessen, K.R. & Richardson, W.D.) 209–220 (BIOS Scientific Publishers, Oxford, UK. 1996).

    Google Scholar 

  3. Noble, M. et al. From rodent glial precursor cell to human glial neoplasia in the oligodendrocyte-type-2 astrocyte lineage. Glia 15, 222–230 (1995).

    Article  CAS  Google Scholar 

  4. Gallo, V. & Ghiani, C.A. Glutamate receptors in glia: New cells, new inputs and new functions. Trends Pharmacol. Sci. 21, 252–258 (2000).

    Article  CAS  Google Scholar 

  5. Chew, L.-J. et al. Growth factor-induced transcription of GluR1 increases functional AMPA receptor density in glial progenitor cells. J. Neurosci. 17, 227–240 (1997).

    Article  CAS  Google Scholar 

  6. Gallo, V., Wright, P. & McKinnon, R.D. Expression and regulation of a glutamate receptor subunit by bFGF in oligodendrocyte progenitor cells. Glia 10, 149–153 (1994).

    Article  CAS  Google Scholar 

  7. Meucci, O., Fatatis, A., Holzwarth, A. & Miller, R.J. Developmental regulation of the toxin sensitivity of Ca2+-permeable AMPA receptors in cortical glia. J. Neurosci. 16, 519–530 (1996).

    Article  CAS  Google Scholar 

  8. Labrakakis, C., Patt, S., Hartmann, J. & Kettenmann, H. Glutamate receptor activation can trigger electrical activity in human glioma cells. Eur. J. Neurosci. 10, 2153–2162 (1998).

    Article  CAS  Google Scholar 

  9. Yoshioka, A., Ikegaki, N., Williams, M. & Pleasure, D. Expression of N-methyl-D-asparate (NMDA) and non-NMDA glutamate receptor genes in neuroblastoma, medulloblastoma, and other cells lines. J. Neurosci. Res. 46, 164–178 (1996).

    Article  CAS  Google Scholar 

  10. Seeburg, P.H. The molecular biology of mammalian glutamate receptor channels. Trends Neurosci. 16, 359–365 (1993).

    Article  CAS  Google Scholar 

  11. Hollmann, M. & Heinemann, S. Cloned glutamate receptors. Annu. Rev. Neurosci. 17, 31–108 (1994).

    Article  CAS  Google Scholar 

  12. Ozawa, S., Kamiya, H. & Tsuzuki, K. Glutamate receptors in the mammalian central nervous system. Prog. Neurobiol. 54, 581–618 (1998).

    Article  CAS  Google Scholar 

  13. Kohara, A. et al. In vitro characterization of YM872, a selective, potent and highly water-soluble α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor antagonist. J. Pharm. Pharmacol. 50, 795–801 (1998).

    Article  CAS  Google Scholar 

  14. Iino, M. et al. Glia-synapse interaction through Ca2+-permeable AMPA receptors in Bergmann glia. Science 292, 926–929 (2001).

    Article  CAS  Google Scholar 

  15. Ishiuchi, S. et al. Extension of glial processes by activation of Ca2+-permeable AMPA receptor channels. Neuroreport 12, 745–748 (2001).

    Article  CAS  Google Scholar 

  16. Cotrina, M.L., Lin, J.H.-C. & Nedergaard, M. Cytoskeletal assembly and ATP release regulate astrocytic calcium signaling. J. Neurosci. 18, 8794–8804 (1998).

    Article  CAS  Google Scholar 

  17. Steller, H. Mechanisms and genes of cellular suicide. Science 267, 1445–1449 (1995).

    Article  CAS  Google Scholar 

  18. Khine, M.M. et al. Analysis of relative proliferation rates of Wilms' tumor components using proliferating cell nuclear antigen and MIB-1 (Ki-67 equivalent antigen) immunostaining and assessment of mitotic index. Lab. Invest. 70, 125–129 (1994).

    CAS  PubMed  Google Scholar 

  19. Gallo, V., Kingsbury, A., Balazs, R. & Jorgensen, O.S. The role of depolarization in the survival and differentiation of cerebellar granule cells in culture. J. Neurosci. 7, 2203–2213 (1987).

    Article  CAS  Google Scholar 

  20. Koike, T., Martin, D.P. & Johnson, E.M. Jr. Role of Ca2+ channels in the ability of membrane depolarization to prevent neuronal death induced by trophic factor deprivation: Evidence that levels of internal Ca2+ determine nerve growth factor dependence of sympathetic ganglion cells. Proc. Natl. Acad. Sci. USA 86, 6421–6425 (1989).

    Article  CAS  Google Scholar 

  21. Yano, S., Tokumitsu, H. & Soderling, T.R. Calcium promotes cell survival through CaM-K kinase activation of the protein-kinase-B pathway. Nature 396, 584–587 (1998).

    Article  CAS  Google Scholar 

  22. Takano, T. et al. Glutamate release promotes growth of malignant gliomas. Nature Med. 7, 1010–1015 (2001).

    Article  CAS  Google Scholar 

  23. Bezzi, P. et al. Prostaglandins stimulate calcium-dependent glutamate release in astrocytes. Nature 391, 281–285 (1998).

    Article  CAS  Google Scholar 

  24. Sasaki, A. et al. Expression of interleukin-1β mRNA and protein in human gliomas assessed by RT-PCR and immunohistochemistry. J. Neuropathol. Exp. Neurol. 57, 653–663 (1998).

    Article  CAS  Google Scholar 

  25. Rzeski, W., Turski, L. & Ikonomidou, C. Glutamate antagonists limit tumor growth. Proc. Natl. Acad. Sci. USA 98, 6372–6377 (2001).

    Article  CAS  Google Scholar 

  26. Ishiuchi, S. & Tamura, M. Central neurocytoma: An immunohistochemical, ultrastructural and cell culture study. Acta Neuropathol. (Berl.) 94, 425–435 (1997).

    Article  CAS  Google Scholar 

  27. Ishiuchi, S. et al. In vitro neuronal and glial production and differentiation of human central neurocytoma cells. J. Neurosci. Res. 51, 526–535 (1998).

    Article  CAS  Google Scholar 

  28. Sakurai, T. & Okada, Y. Selective reduction of glutamate in the rat superior colliculus and dorsal lateral geniculate nucleus after contralateral enucleation. Brain Res. 573, 197–203 (1992).

    Article  CAS  Google Scholar 

  29. Miyake, S. et al. Efficient generation of recombinant adenoviruses using DNA-terminal protein complex and a cosmid bearing the full-length virus genome. Proc. Natl. Acad. Sci. USA 93, 1320–1324 (1996).

    Article  CAS  Google Scholar 

  30. Kanegae, Y. et al. Efficient gene activation in mammalian cells by using recombinant adenovirus expressing site-specific Cre recombinase. Nucl. Acids Res. 23, 3816–3821 (1995).

    Article  CAS  Google Scholar 

  31. Sudo, M. et al. Postsynaptic expression of Ca2+-permeable AMPA-type glutamate receptor channels by viral-mediated gene transfer. Mol. Brain Res. 65, 176–85 (1999).

    Article  CAS  Google Scholar 

  32. Nakazato, Y., Ishida, Y., Takahashi K. & Suzuki, K. Immunohistochemical distribution of S-100 protein and glial fibrillary acidic protein in normal and neoplastic salivary glands. Virchows Arch. A Pathol. Anat. Histopathol. 405, 299–310 (1985).

    Article  CAS  Google Scholar 

  33. Kondo, M., Sumino, R. & Okado, H. Combinations of AMPA receptor subunit expression in individual cortical neurons correlate with expression of specific calcium-binding proteins. J. Neurosci. 17, 1570–1581 (1997).

    Article  CAS  Google Scholar 

  34. Mogami, H., Nakano, K., Tepikin, A.V. & Petersen, O.H. Ca2+ flow via tunnels in polarized cells: recharging of apical Ca2+ stores by focal Ca2+ entry through basal membrane patch. Cell 88, 49–55 (1997).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank I. Saito and Y. Kanegae for materials for constructing recombinant adenoviruses; M. Kondo for DNA templates for GluR1 and GluR2 to produce RNA probes for in situ hybridization; and M. Maniwa for technical assistance.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Gunma University School of Medicine, Maebashi, Gunma, Japan

    Shogo Ishiuchi, Hideyuki Kurihara & Masaru Tamura

  2. Department of Physiology, Gunma University School of Medicine, Maebashi, Gunma, Japan

    Keisuke Tsuzuki, Yukari Yoshida, Nobuaki Yamada, Norikazu Hagimura & Seiji Ozawa

  3. Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Kawaguchi, Saitama, Japan

    Shogo Ishiuchi, Keisuke Tsuzuki, Yukari Yoshida, Nobuaki Yamada, Norikazu Hagimura, Haruo Okado, Akiko Miwa & Seiji Ozawa

  4. Department of Neurobiology, Tokyo Metropolitan Institute for Neuroscience, Fuchu, Japan

    Haruo Okado & Akiko Miwa

  5. Department of Pathology, Gunma University School of Medicine, Maebashi, Gunma, Japan

    Yoichi Nakazato

  6. Department of Neurosurgery, Kyushu University School of Medicine, Fukuoka, Japan

    Tomio Sasaki

Authors
  1. Shogo Ishiuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Keisuke Tsuzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yukari Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nobuaki Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Norikazu Hagimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Haruo Okado
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Akiko Miwa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hideyuki Kurihara
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yoichi Nakazato
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Masaru Tamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Tomio Sasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Seiji Ozawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shogo Ishiuchi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ishiuchi, S., Tsuzuki, K., Yoshida, Y. et al. Blockage of Ca2+-permeable AMPA receptors suppresses migration and induces apoptosis in human glioblastoma cells. Nat Med 8, 971–978 (2002). https://doi.org/10.1038/nm746

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm746

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing