Propentofylline targets TROY, a novel microglial signaling pathway

PLoS One. 2012;7(5):e37955. doi: 10.1371/journal.pone.0037955. Epub 2012 May 23.

Abstract

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain cancer, with a median survival of less than 2 years after diagnosis with current available therapies. The tumor microenvironment serves a critical role in tumor invasion and progression, with microglia as a critical player. Our laboratory has previously demonstrated that propentofylline, an atypical methylxanthine with central nervous system glial modulating and anti-inflammatory actions, significantly decreases tumor growth in a GBM rodent model by preferentially targeting microglia. In the present study, we used the CNS-1 rat glioma model to elucidate the mechanisms of propentofylline. Here we demonstrate that propentofylline targets TROY, a novel signaling molecule up-regulated in infiltrating microglia, and not macrophages, in response to CNS-1 cells. We identify Pyk2, Rac1 and pJNK as the downstream signaling molecules of TROY through western blot analysis and siRNA transfection. We demonstrate that inhibition of TROY expression in microglia by siRNA transfection significantly inhibits microglial migration towards CNS-1 cells similar to 10 µM propentofylline treatment. These results identify TROY as a novel molecule expressed in microglia, involved in their migration and targeted by propentofylline. Furthermore, these results describe a signaling molecule that is differentially expressed between microglia and macrophages in the tumor microenvironment.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Movement / drug effects
  • Cell Movement / physiology
  • Flow Cytometry
  • Focal Adhesion Kinase 2 / metabolism
  • Glioblastoma / drug therapy
  • Glioblastoma / physiopathology*
  • Immunohistochemistry
  • Microglia / drug effects
  • Microglia / metabolism
  • Microglia / physiology*
  • Neuropeptides / metabolism
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Rats
  • Receptors, Tumor Necrosis Factor / metabolism*
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Xanthines / pharmacology*
  • Xanthines / therapeutic use
  • rac GTP-Binding Proteins / metabolism
  • rac1 GTP-Binding Protein

Substances

  • Neuropeptides
  • RNA, Small Interfering
  • Rac1 protein, mouse
  • Receptors, Tumor Necrosis Factor
  • Tnfrsf19 protein, mouse
  • Xanthines
  • propentofylline
  • Focal Adhesion Kinase 2
  • Ptk2b protein, mouse
  • rac GTP-Binding Proteins
  • rac1 GTP-Binding Protein