gms | German Medical Science

60. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
Joint Meeting mit den Benelux-Ländern und Bulgarien

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

24. - 27.05.2009, Münster

Inhibition of the JAK/STAT3 pathway constrains the migratory, invasive, and proliferative behavior of glioblastoma cells

Meeting Abstract

  • C. Senft - Klinik und Poliklinik für Neurochirurgie, Johann Wolfgang Goethe-Universität, Frankfurt am Main
  • M. Priester - Experimentelle Neurochirurgie, Klinik für Neurochirurgie, Johann Wolfgang Goethe-Universität, Frankfurt am Main
  • V. Seifert - Klinik und Poliklinik für Neurochirurgie, Johann Wolfgang Goethe-Universität, Frankfurt am Main
  • D. Kögel - Experimentelle Neurochirurgie, Klinik für Neurochirurgie, Johann Wolfgang Goethe-Universität, Frankfurt am Main
  • J. Weissenberger - Experimentelle Neurochirurgie, Klinik für Neurochirurgie, Johann Wolfgang Goethe-Universität, Frankfurt am Main

Deutsche Gesellschaft für Neurochirurgie. 60. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit den Benelux-Ländern und Bulgarien. Münster, 24.-27.05.2009. Düsseldorf: German Medical Science GMS Publishing House; 2009. DocP14-05

DOI: 10.3205/09dgnc403, URN: urn:nbn:de:0183-09dgnc4038

Veröffentlicht: 20. Mai 2009

© 2009 Senft 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 vervielfältigt, verbreitet und öffentlich zugänglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

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Objective: Current treatment strategies for malignant gliomas primarily aim at cytoreduction. Recurrences are common and present quite distantly from the primary tumor site. Therefore we need therapies that foremost tackle the pivotal hallmark of gliomas i.e. to diffusely infiltrate and invade the healthy brain parenchyma. Signal transducer and activator of transcription 3 (STAT3) plays a key role in the cellular signaling cascade mediated through Janus-activated kinases (JAK) and is known to be involved in cell proliferation, cell migration and invasion.

Methods: Two different JAK/STAT3-inhibitory substances, tyrphostin and curcumin, were used to study the effects on glioma cell proliferation, migration, and invasion in five glioblastoma cell lines in vitro. Downregulation of the biologically active, phosphorylated STAT3 was determined by Western blot analyses and Phospho-STAT3 (Tyr705) Sandwich ELISA. Functional readouts were performed by employing MTT, monolayer wound-healing, and modified Boyden-chamber assays.

Results: Both tyrphostin and curcumin led to a downregulation of phospho-STAT3 in a time- and dose-dependent fashion in all cell lines tested. The decrease of intracellular phospho-STAT3 levels correlated with a marked reduction of migratory and invasive behavior in all five cell lines. While STAT3 inactivation by curcumin was already evident 2h after treatment, a longer incubation time (48h) was necessary for tyrphostin. In particular, inhibition of JAK/STAT3 signaling down-modulated mRNA transcripts of the STAT3 target gene MMP-2 in all investigated cell lines. In addition to the antimigratory and anti-invasive effect, both substances exhibited a potent antiproliferative effect in all five glioblastoma cell lines.

Conclusions: Since pharmacological inhibition of the JAK/STAT3 signaling pathway does not only affect tumor cell proliferation but also the central pathognomonic feature of malignant gliomas, i.e. diffuse infiltration pertinent to frequent tumor recurrence and high morbidity, our findings support the idea of targeting STAT3 in the treatment of brain tumors.