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Journal of Neuro-Oncology

, Volume 101, Issue 3, pp 393–403 | Cite as

Inhibition of the JAK-2/STAT3 signaling pathway impedes the migratory and invasive potential of human glioblastoma cells

  • Christian Senft
  • Maike Priester
  • Margareth Polacin
  • Katrin Schröder
  • Volker Seifert
  • Donat Kögel
  • Jakob Weissenberger
Laboratory Investigation - Human/Animal Tissue

Abstract

The objective of current treatment strategies for glioblastoma (GBM) is cytoreduction. Unfortunately, the deleterious migratory and invasive behavior of glial tumors remains largely unattended. The transcription factor signal transducer and activator of transcription (STAT) 3 is known to be involved in the development and progression of many different tumor types, including malignant gliomas. Beside other biological effects, STAT3 controls cell proliferation and tissue remodeling, processes common to both wound healing and tumor dissemination. Here, we report on impeded migratory and invasive potential of five different glioblastoma cell lines after treatment with AG490, a pharmacological inhibitor of the upstream STAT3 activator Janus kinase (JAK) 2. STAT3 was constitutively activated in all the cell lines tested, and treatment with AG490 eliminated the biologically active, tyrosine705-phosphorylated form of STAT3 in a dose-dependent fashion, as determined by Western blot analysis. Inhibition of activated STAT3 was paralleled by a decrease in transcriptional expression of the STAT3 target genes MMP-2 and MMP-9, and led to reduced proteolytic activity, as determined by zymography. Accordingly, the migratory behavior of all five GBM cell lines was impeded in monolayer wound-healing assays; invasive capacity in matrigel-coated trans-well assays was also hampered by treatment with AG490. The proliferative activity of the cell lines was also significantly reduced after treatment with AG490. The effects elicited by STAT3 inhibition were observed in both PTEN-expressing and PTEN-deficient cells. Because pharmacological inhibition of the JAK-2/STAT3 signaling pathway affects not only tumor cell proliferation but also the characteristic features of malignant gliomas, i.e. migration and invasion pertinent to invariable tumor recurrence and high morbidity, our findings support the idea that STAT3 is a suitable target in the treatment of brain tumors.

Keywords

Glioblastoma Migration Invasion STAT3 

Abbreviations

ECL

Enhanced chemiluminescence

IL-6

Interleukin-6

RIPA

Radioimmunoprecipitation assay

Ras

Proto-oncogene, small GTPase

Src

Proto-oncogene, non-receptor tyrosine kinase

SDS

Sodium dodecyl sulfate

PAGE

Polyacrylamide gel electrophoresis

BCA

Bicinchoninic acid

PTEN

Phosphatase and tensin homolog

BSA

Bovine serum albumin

Notes

Acknowledgments

The authors would like to thank C. Geist and H. Schweers, for excellent technical assistance, and M. Eberhardt, for assisting with the preparation of the figures. This work was financially supported by the Deutsche Forschungsgemeinschaft (DFG), grant # WE 4358/1-1 to JW and DK.

Conflicts of interest statement

The authors report no conflict of interest concerning the materials or methods used in this study or the findings reported in this paper.

Supplementary material

11060_2010_273_MOESM1_ESM.pdf (1.1 mb)
Supplementary material 1 (PDF 1083 kb)

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Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Christian Senft
    • 1
    • 2
  • Maike Priester
    • 2
  • Margareth Polacin
    • 2
  • Katrin Schröder
    • 3
  • Volker Seifert
    • 1
  • Donat Kögel
    • 2
  • Jakob Weissenberger
    • 2
  1. 1.Department of NeurosurgeryGoethe-UniversityFrankfurtGermany
  2. 2.Experimental Neurosurgery, Neuroscience CenterGoethe-UniversityFrankfurtGermany
  3. 3.Institute of Cardiovascular PhysiologyGoethe-UniversityFrankfurtGermany

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