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Transferrin-receptor-mediated iron accumulation controls proliferation and glutamate release in glioma cells

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Abstract

Transferrin receptors (TfR) are overexpressed in brain tumors, but the pathological relevance has not been fully explored. Here, we show that TfR is an important downstream effector of ets transcription factors that promotes glioma proliferation and increases glioma-evoked neuronal death. TfR mediates iron accumulation and reactive oxygen formation and thereby enhanced proliferation in clonal human glioma lines, as shown by the following experiments: (1) downregulating TfR expression reduced proliferation in vitro and in vivo; (2) forced TfR expression in low-grade glioma accelerated proliferation to the level of high-grade glioma; (3) iron and oxidant chelators attenuated tumor proliferation in vitro and tumor size in vivo. TfR-induced oxidant accumulation modified cellular signaling by inactivating a protein tyrosine phosphatase (low-molecular-weight protein tyrosine phosphatase), activating mitogen-activated protein kinase and Akt and by inactivating p21/cdkn1a and pRB. Inactivation of these cell cycle regulators facilitated S-phase entry. Besides its effect on proliferation, TfR also boosted glutamate release, which caused N-methyl-d-aspartate-receptor-mediated reduction of neuron cell mass. Our results indicate that TfR promotes glioma progression by two mechanisms, an increase in proliferation rate and glutamate production, the latter mechanism providing space for the progressing tumor mass.

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Acknowledgements

We would like to thank Dr. L. Kühn (ISREC, Epalinges, Switzerland), Dr. M Gossen (Max Delbrück Center, Berlin, Germany), and Dr. H. Sato (Kanazawa University; Kanzawa, Japan) for providing us with expression plasmids.

The research was supported by Bundesministerium für Forschung und Technologie (H. K.); J.C.M and S.A.E. were financed by grants from the DFG (ME2075/3-1 and Sonderforschungsbereich Grant TR3/B5 to JCM) and Helmholtz Association (VH-NG-246 to JCM).

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Authors and Affiliations

  1. Cellular Neuroscience Group, Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany

    S. R. Chirasani, D. S. Markovic, H. Kettenmann & R. Glass

  2. Department of Neurosurgery, Charite University Hospital, Berlin, Germany

    M. Synowitz

  3. RNA Editing and Hyperexcitability Group, Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany

    S. A. Eichler & J. C. Meier

  4. Laboratory of Transcription Regulation, Department of Cell Biology, Nencki Institute of Experimental Biology, Warsaw, Poland

    P. Wisniewski & B. Kaminska

  5. Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, MaxDelbrück Center for Molecular Medicine (MDC), Berlin, Germany

    A. Otto & E. Wanker

  6. Insitute of Anatomy and Cell Biology, University of Freiburg, Freiburg, Germany

    M. Schäfer

  7. Department of Biochemical Sciences, University of Florence, Florence, Italy

    P. Chiarugi

  8. Department for Neurosurgery, Helios Klinikum, Schwanebecker Chaussee 50, 13125, Berlin, Germany

    D. S. Markovic

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  1. S. R. Chirasani
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Correspondence to R. Glass.

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H. Kettenmann and R. Glass contributed equally to this work.

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Chirasani, S.R., Markovic, D.S., Synowitz, M. et al. Transferrin-receptor-mediated iron accumulation controls proliferation and glutamate release in glioma cells. J Mol Med 87, 153–167 (2009). https://doi.org/10.1007/s00109-008-0414-3

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  • DOI: https://doi.org/10.1007/s00109-008-0414-3

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