Mutant IDH1 inhibits PI3K/Akt signaling in human glioma

Authors

  • Peter Birner MD,

    1. Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany
    2. Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria
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  • Stefan Pusch PhD,

    1. Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany
    2. Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany
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  • Christo Christov MD,

    1. Department of Neurosurgery, St. Ivan Rilski Hospital, Sofia, Bulgaria
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  • Stiliana Mihaylova MD,

    1. Department of Neurosurgery, St. Ivan Rilski Hospital, Sofia, Bulgaria
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  • Kalina Toumangelova-Uzeir MS,

    1. Department of Neuropathology, St. Ivan Rilski Hospital, Sofia, Bulgaria
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  • Sevdalin Natchev MD,

    1. Department of Neuropathology, St. Ivan Rilski Hospital, Sofia, Bulgaria
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  • Sebastian F. Schoppmann MD,

    1. Department of Surgery, Medical University of Vienna, Vienna, Austria
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  • Andrey Tchorbanov PhD,

    1. Department of Immunology, Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, Bulgaria
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  • Berthold Streubel MD,

    Corresponding author
    1. Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria
    • Corresponding authors : Marin Guentchev, Department of Neurosurgery, Klinikum Idar-Oberstein, Dr. Ottmar-Kohler Str. 2, 55743 Idar-Oberstein, Germany; Fax: (011) +49/6781/661562; guentchev@gmail.com; Berthold Streubel, Department of Obstetrics and Gynecology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria; Fax: (011) 43 1 404 00-2820; berthold.streubel@meduniwien.ac.at.

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  • Jochen Tuettenberg MD,

    1. Department of Neurosurgery, Klinikum Idar-Oberstein, Idar-Oberstein, Germany
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    • Drs. Guentchev and Tuettenberg share senior authorship.

  • Marin Guentchev MD

    Corresponding author
    1. Department of Neurosurgery, Klinikum Idar-Oberstein, Idar-Oberstein, Germany
    • Corresponding authors : Marin Guentchev, Department of Neurosurgery, Klinikum Idar-Oberstein, Dr. Ottmar-Kohler Str. 2, 55743 Idar-Oberstein, Germany; Fax: (011) +49/6781/661562; guentchev@gmail.com; Berthold Streubel, Department of Obstetrics and Gynecology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria; Fax: (011) 43 1 404 00-2820; berthold.streubel@meduniwien.ac.at.

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    • Drs. Guentchev and Tuettenberg share senior authorship.


  • We are grateful to Andreas von Deimling, Pieter Wesseling, and Herbert Budka for critical discussions and support. We thank Gerda Ricken and Milena Moneva for excellent technical assistance. The kind support of David Reuss is highly appreciated.

Abstract

BACKGROUND

Recently, isocitrate dehydrogenase 1 (IDH1) was identified as a major participant in glioma pathogenesis. At present, the enzymatic activity of the protein has been the main topic in investigating its physiological function, but its signaling pathway allocation was unsuccessful. Interestingly, proteins regulated by phosphoinositide 3-kinase (PI3K)/Akt signaling, are among the top downregulated genes in gliomas associated with high percentage of IDH1 and IDH2 mutations. The aim of this study was to investigate a hypothetical relation between IDH1 and PI3K signaling.

METHODS

The presence of mutant IDH1 and markers for active PI3K/Akt signaling, present as phosphorylated Akt and podoplanin (PDPN), were investigated in a discovery cohort of 354 patients with glioma. In vitro experiments were used to confirm functional links.

RESULTS

This study shows an inverse correlation between mutant IDH1 and markers for active PI3K/Akt signaling. In support of a functional link between these molecules, in vitro expression of mutant IDH1 inhibited Akt phosphorylation in a 2-hydroxyglutarate–dependent manner.

CONCLUSIONS

This study provides patient tumor and in vitro evidence suggesting that mutant IDH1 inhibits PI3K/Akt signaling. Cancer 2014;120:2440–2447. © 2014 American Cancer Society.

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