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The PEA-15/PED protein protects glioblastoma cells from glucose deprivation-induced apoptosis via the ERK/MAP kinase pathway

Oncogene volume 27, pages 1155–1166 (2008)Cite this article

Abstract

PEA-15 (phosphoprotein enriched in astrocytes 15 kDa) is a death effector domain-containing protein, which is involved in the regulation of apoptotic cell death. Since PEA-15 is highly expressed in cells of glial origin, we studied the role of PEA-15 in human malignant brain tumors. Immunohistochemical analysis of PEA-15 expression shows strong immunoreactivity in astrocytomas and glioblastomas. Phosphorylation of PEA-15 at Ser116 is found in vivo in perinecrotic areas in glioblastomas and in vitro after glucose deprivation of glioblastoma cells. Overexpression of PEA-15 induces a marked resistance against glucose deprivation-induced apoptosis, whereas small interfering RNA (siRNA)-mediated downregulation of endogenous PEA-15 results in the sensitization to glucose withdrawal-mediated cell death. This antiapoptotic activity of PEA-15 under low glucose conditions depends on its phosphorylation at Ser116. Moreover, siRNA-mediated knockdown of PEA-15 abolishes the tumorigenicity of U87MG glioblastoma cells in vivo. PEA-15 regulates the level of phosphorylated extracellular-regulated kinase (ERK)1/2 in glioblastoma cells and the PEA-15-dependent protection from glucose deprivation-induced cell death requires ERK1/2 signaling. PEA-15 transcriptionally upregulates the Glucose Transporter 3, which is abrogated by the inhibition of ERK1/2 phosphorylation. Taken together, our findings suggest that Ser116-phosphorylated PEA-15 renders glioma cells resistant to glucose deprivation-mediated cell death as encountered in poor microenvironments, for example in perinecrotic areas of glioblastomas.

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Acknowledgements

This work was supported by a grant from the Deutsche Krebshilfe to WR (German Cancer Aid, Max Eder Program). We thank Ilona Demir and Karina Zipp for expert technical assistance and Christine Golde and Ulrike Lemke for advice.

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Author notes

  1. A Eckert and B C Böck: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular Neuro-Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany

    A Eckert, B C Böck, K E Tagscherer, K Grund, O D Wiestler & W Roth

  2. Division of Apoptosis Regulation, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany

    T L Haas, J Sykora & H Walczak

  3. Division of Neurosurgical Research, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany

    C Herold-Mende

  4. Institute of Pathology, University of Heidelberg, Heidelberg, Germany

    V Ehemann & W Roth

  5. Department of Genetic Alterations in Carcinogenesis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany

    M Hollstein

  6. INSERM U752, Centre Paul Broca, Paris, France

    H Chneiweiss

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Correspondence to W Roth.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Eckert, A., Böck, B., Tagscherer, K. et al. The PEA-15/PED protein protects glioblastoma cells from glucose deprivation-induced apoptosis via the ERK/MAP kinase pathway. Oncogene 27, 1155–1166 (2008). https://doi.org/10.1038/sj.onc.1210732

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