gms | German Medical Science

58. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie e. V. (DGNC)

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

26. bis 29.04.2007, Leipzig

Pharmacological inhibition of the signal transducer and activator of transcription 3 (Stat3) pathway in malignant glioma cells

Pharmakologische Inhibition der Stat3-Signalkaskade in humanen Glioblastomzellen

Meeting Abstract

  • corresponding author J. Weissenberger - Abt. Experimentelle Neurochirurgie, Johann-Wolfgang-Goethe-Universität, Frankfurt am Main
  • J. Masri - Abt. Experimentelle Neurochirurgie, Johann-Wolfgang-Goethe-Universität, Frankfurt am Main
  • H. Hetschko - Abt. Experimentelle Neurochirurgie, Johann-Wolfgang-Goethe-Universität, Frankfurt am Main
  • C. Senft - Klinik für Neurochirurgie, Johann-Wolfgang-Goethe-Universität, Frankfurt am Main
  • A. Raabe - Klinik für Neurochirurgie, Johann-Wolfgang-Goethe-Universität, Frankfurt am Main
  • V. Seifert - Klinik für Neurochirurgie, Johann-Wolfgang-Goethe-Universität, Frankfurt am Main
  • D. Kögel - Abt. Experimentelle Neurochirurgie, Johann-Wolfgang-Goethe-Universität, Frankfurt am Main

Deutsche Gesellschaft für Neurochirurgie. 58. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie e.V. (DGNC). Leipzig, 26.-29.04.2007. Düsseldorf: German Medical Science GMS Publishing House; 2007. DocFR.09.09

Die elektronische Version dieses Artikels ist vollständig und ist verfügbar unter: http://www.egms.de/de/meetings/dgnc2007/07dgnc130.shtml

Veröffentlicht: 11. April 2007

© 2007 Weissenberger et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielf&aauml;ltigt, verbreitet und &oauml;ffentlich zug&aauml;nglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

Text

Objective: The transcription factor Stat3 is overexpressed and overactivated in many neoplasms including malignant gliomas. Constitutively active Stat3 promotes proliferation, survival, and cell motility. We have recently shown that the activation level of Stat3 correlates with malignancy. Therefore, we sought to inhibit Stat3 signalling by administration of pharmacological inhibitors to test whether blocking the Stat3 pathway might display therapeutic effects.

Methods: We treated human GBM cells in vitro with three different inhibitors (AG490, SU6656, and Curcumin) known to interfere with Jak/Stat- and Src-signalling, which have been shown to be constitutively activated in GBMs. Inhibition of Stat3 activity was analyzed by Western Blotting. Reduction of migration of GBM cells was assessed by wound healing assays. Apoptosis was measured by FACS analysis and caspase-3 assays.

Results: We analyzed the Stat3-activation level in 6 GBM cell lines. All but one cell line showed increased levels of phosphorylated Stat3 (pY-Stat3). 100μM of AG490 reduced pY-Stat3 levels three-fold within 48 hrs. We further tested, whether AG490-induced downregulation of Stat3 activity affected apoptosis resistance. We could show that combination of AG490 and TRAIL (TNF-related apoptosis inducing ligand) had a five-fold synergistic effect on apoptosis induction compared to solitary treatment. AG490 also efficiently reduced the migratory potential of GBM cells by 50%. The inhibitory effect of the Src kinase inhibitor SU6656 on Stat3 phosphorylation varied among the cell lines indicating that Stat3 activation is not strictly Src-dependent. Curcumin proved to be the most potent inhibitor of Stat3 phosphorylation. A concentration of 20μM Curcumin administered for 24 hrs was sufficient to abolish Stat3 phosphorylation. This potent inhibition of Stat3 by Curcumin was associated with massive apoptosis.

Conclusions: Pharmacological inhibitors were found to efficiently suppress Stat3 activation, thus inducing apoptosis and reducing cell motility. Upcoming experiments will disclose the consequences of pharmacological Stat3 inhibition on cell proliferation and infiltration, providing novel insights into the suitability of Stat3 inhibitors as therapeutic agents for the treatment of malignant gliomas.