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Small interfering RNA–mediated xCT silencing in gliomas inhibits neurodegeneration and alleviates brain edema

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Abstract

Neurodegeneration and brain edema are hallmarks of human malignant brain tumors. Here we show that genetic or pharmacological inhibition of the glutamate transporter xCT (Xc− system, encoded by SLC7a11) in vivo leads to abrogated neurodegeneration, attenuated perifocal edema and prolonged survival. These results show a crucial role for xCT in glioma-induced neurodegeneration and brain edema, corroborating the concept that edema formation may be in part a consequence of peritumoral cell death.

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Figure 1: Human gliomas show elevated xCT expression, and siRNA-mediated xCT silencing lessens neurotoxic glutamate abundance in vivo.
Figure 2: RNAi-mediated xCT silencing or pharmacological xCT inhibition alleviates tumor-induced brain edema and prolongs survival.

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Acknowledgements

We thank N. Scheufler, J. Csupor, S. Seufert, R. Schneider and H. Hilkman for experimental support. We further thank P.W. Kalivas (Medical University of South Carolina, Charleston, USA) for the antibody to xCT antibody and for sharing unpublished data, M. Conrad (German Research Center for Environmental Health, München, Germany) for the human and mouse xCT expression constructs, B.I. Kanner (Hebrew University Jerusalem, Israel) and G. Pietrini (Consiglio Nazionale delle Ricerche, Milano, Italy) for the GLT-1 expression construct and H. Sontheimer for providing details on the glutamate estimation. We acknowledge F. Mouttet and D. Peleg-Raibstein for technical support. We gratefully acknowledge members of M. Schwab's laboratory, J.R. Halstead and members of the H3 lab for helpful comments on the manuscript. E.H. is supported by the Köln Fortune Program of the Medical Faculty University Cologne and the Wilhelm Sander-Stiftung (WSS 2008.010.1). This study was funded by The International Human Frontiers Science Program Organization (to N.E.S.) and the Wilhelm Sander-Stiftung (WSS 2005.089.1 to I.Y.E.).

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Authors and Affiliations

  1. Brain Research Institute, Swiss Federal Institute of Technology & University Zurich, Winterthurerstrasse 190, Zurich, CH-8057, Switzerland

    Nicolai E Savaskan

  2. Division of Cellular Biochemistry, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, NL-1066 CX, The Netherlands

    Nicolai E Savaskan

  3. Department of Neurosurgery, University of Erlangen-Nuremberg, Schwabachanlage 6, D-91054, Erlangen, Germany

    Alexandra Heckel, Oliver Ganslandt, Christopher Nimsky, Michael Buchfelder & Ilker Y Eyüpoglu

  4. Institute of Human Genetics, Institute of Genetics and Center for Molecular Medicine Cologne, University of Cologne, Zülpicherstrasse 47, D-50674, Cologne, Germany

    Eric Hahnen

  5. Department of Neuropathology, University of Erlangen-Nuremberg, Schwabachanlage 6, D-91054, Erlangen, Germany

    Eric Hahnen

  6. Department of Neuroradiology, University of Erlangen-Nuremberg, Schwabachanlage 6, D-91054, Erlangen, Germany

    Tobias Engelhorn & Arnd Doerfler

Authors
  1. Nicolai E Savaskan
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  2. Alexandra Heckel
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  3. Eric Hahnen
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  4. Tobias Engelhorn
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  5. Arnd Doerfler
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  6. Oliver Ganslandt
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  7. Christopher Nimsky
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  8. Michael Buchfelder
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  9. Ilker Y Eyüpoglu
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Contributions

N.E.S. and I.Y.E. conceived and designed the experiments; N.E.S., A.H., E.H. and I.Y.E. performed the in vitro experiments and contributed to the molecular cloning; N.E.S., T.E. and I.Y.E. performed the in vivo experiments; N.E.S., E.H., A.D., O.G., C.N., M.B. and I.Y.E. analyzed the data and contributed to techniques and analysis systems; N.E.S. and I.Y.E. wrote and edited the manuscript.

Corresponding authors

Correspondence to Nicolai E Savaskan or Ilker Y Eyüpoglu.

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Supplementary Text and Figures

Supplementary Figs. 1–5 and Supplementary Methods (PDF 682 kb)

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Savaskan, N., Heckel, A., Hahnen, E. et al. Small interfering RNA–mediated xCT silencing in gliomas inhibits neurodegeneration and alleviates brain edema. Nat Med 14, 629–632 (2008). https://doi.org/10.1038/nm1772

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  • DOI: https://doi.org/10.1038/nm1772

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