gms | German Medical Science

59th Annual Meeting of the German Society of Neurosurgery (DGNC)
3rd Joint Meeting with the Italian Neurosurgical Society (SINch)

German Society of Neurosurgery (DGNC)

1 - 4 June 2008, Würzburg

Activation of the Wnt/beta-catenin pathway in malignant gliomas and its modulation through suberoylanilide hydroxamic acid (SAHA)

Aktivierung des Wnt/beta-catenin Signalweges in malignen Gliomen und seine Modulierung durch suberoylanilide hydroxamic Säure (SAHA)

Meeting Abstract

  • corresponding author N. Kremenevskaya - Department of Neurosurgery, University of Erlangen-Nürnberg, Erlangen
  • E. Hahnen - Institute of Human Genetics, University of Cologne, Cologne, Germany
  • M. N. K. Khattak - Department of Neurosurgery, University of Erlangen-Nürnberg, Erlangen
  • M. Buchfelder - Department of Neurosurgery, University of Erlangen-Nürnberg, Erlangen
  • I. Y. Eyüpoglu - Department of Neurosurgery, University of Erlangen-Nürnberg, Erlangen

Deutsche Gesellschaft für Neurochirurgie. Società Italiana di Neurochirurgia. 59. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie e.V. (DGNC), 3. Joint Meeting mit der Italienischen Gesellschaft für Neurochirurgie (SINch). Würzburg, 01.-04.06.2008. Düsseldorf: German Medical Science GMS Publishing House; 2008. DocP 001

The electronic version of this article is the complete one and can be found online at: http://www.egms.de/en/meetings/dgnc2008/08dgnc269.shtml

Published: May 30, 2008

© 2008 Kremenevskaya et al.
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Outline

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Objective: Altered Wnt/β-catenin signaling has been recognized to contribute to the development of various human cancers. Wnt stabilizes β-catenin by preventing its phosphorylation which targets β-catenin for degradation. Free β-catenin is translocated to the nucleus where it stimulates a number of genes that modulate proliferation and differentiation upon binding to TCF/LEF. However, its role in brain malignancies such as malignant gliomas is only marginally described. Moreover, therapeutic regimes for this tumor entity are limited. In this context, the histone deacetylases (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) has been shown to have potent antiglioma potency. The mechanisms remain largely unclear. In this study, we therefore analyzed a potential role of the Wnt/β-catenin pathway in malignant gliomas and its modulation through SAHA.

Methods: The U87 and U373 human glioma cell lines, the SMA-560 and GL261 mouse glioma cell lines and tumor samples from 10 patients suffering from glioblastoma multiforme were studied by Western blot analyses, immunohistochemistry and RT-PCR for the expression of β-catenin, TCF-4 and cyclin D1. The effect of SAHA on expression of these factors and cell growth were studied in U87, U373, SMA-560 and GL261 cell lines. Moreover, cell lines were transfected with different plasmids modulating relevant steps in Wnt signaling.

Results: Compared to normal tissue cytoplasmatic β-catenin, nuclear TCF-4 and cyclin D1 expression were increased in glioblastoma multiforme tumor samples. Transfection of U373 and U87 glioma cell lines with dnTCF-4 resulted in a reduced proliferation, indicating that Wnt signaling plays a relevant role in glioma progression. In contrast, transfection of these cell lines with wtTCF-4 induced a significantly increased proliferation activity. In the next set of experiments, we tested whether SAHA might modulate Wnt signaling in malignant gliomas. In almost all analyzed glioma cell lines the administration of SAHA inhibited tumor cell growth in a therapeutic range of 1–10 µM. This effect of SAHA was associated with decreased β-catenin, TCF-4 and cyclin D1 expression both at RNA and protein levels. While transfection with wtTCF-4 increased proliferation activity, this effect was blocked by SAHA treatment.

Conclusions: Our data indicate that the Wnt/β-catenin signaling pathway is deregulated in malignant gliomas and is essential in glioma survival. Moreover, HDAC inhibitors such as SAHA may block glioma progression via modulation of the Wnt/β-catenin signaling pathway.