Inhibition of NF-κB Signaling Ablates the Invasive Phenotype of Glioblastoma

Mike-Andrew Westhoff, Shaoxia Zhou, Lisa Nonnenmacher, Georg Karpel-Massler, Claudia Jennewein, Matthias Schneider, Marc-Eric Halatsch, Neil O. Carragher, Bernd Baumann, Alexander Krause, Thomas Simmet, Max G. Bachem, Christian R. Wirtz, Klaus-Michael Debatin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Glioblastoma Multiforme (GBM), the most common primary brain tumor, is highly refractory to therapy, mainly due to its ability to form micrometastases, which are small clusters or individual cells that rapidly transverse the brain and make full surgical resection impossible. Here it is demonstrated that the invasive phenotype of GBM is orchestrated by the transcription factor NF-κB which, via metalloproteinases (MMPs), regulates Fibronectin (Fn) processing. Both, cell lines and tumor stem cells from primary GBM, secrete high levels of Fn and when cleaved by MMPs form an extracellular substrate. Subsequently, forming and interacting with their own microenvironment, GBM cells are licensed to invade their surroundings. Mechanistic study revealed that NF-κB inhibition, either genetically or pharmacologically, by treatment with Disulfiram, significantly abolished the invasive phenotype in the chick chorioallantoic membrane (CAM) assay. Furthermore, having delineated the underlying molecular mechanism of GBM invasion, the potential of a Disulfiram-based therapy was revealed in a highly invasive orthotrophic GBM mouse model. Implications: This study defines a novel therapeutic approach that inhibits micrometastases invasion and reverts lethal Glioblastoma into a less aggressive disease.
Original languageEnglish
Pages (from-to)1611-1623
Number of pages13
JournalMolecular Cancer Research
Volume11
Issue number12
DOIs
Publication statusPublished - Dec 2013

Keywords

  • PLASMINOGEN-ACTIVATOR RECEPTOR
  • CANCER CELL-LINES
  • GENE-EXPRESSION
  • MATRIX METALLOPROTEINASES
  • INDUCED APOPTOSIS
  • MALIGNANT GLIOMA
  • DOWN-REGULATION
  • IN-VIVO
  • IDENTIFICATION
  • FIBRONECTIN

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