Probing the infiltrating character of brain tumors: inhibition of RhoA/ROK-mediated CD44 cell surface shedding from glioma cells by the green tea catechin EGCg

J Neurochem. 2005 Aug;94(4):906-16. doi: 10.1111/j.1471-4159.2005.03256.x. Epub 2005 Jun 30.

Abstract

Glioma cell-surface binding to hyaluronan (HA), a major constituent of the brain extracellular matrix (ECM) environment, is regulated through a complex membrane type-1 matrix metalloproteinase (MT1-MMP)/CD44/caveolin interaction that takes place at the leading edges of invading cells. In the present study, intracellular transduction pathways required for the HA-mediated recognition by infiltrating glioma cells in brain was investigated. We show that the overexpression of the GTPase RhoA up-regulated MT1-MMP expression and triggered CD44 shedding from the U-87 glioma cell surface. This potential implication in cerebral metastatic processes was also observed in cells overexpressing the full-length recombinant MT1-MMP, while the overexpression of a cytoplasmic domain truncated from of MT1-MMP failed to do so. This suggests that the cytoplasmic domain of MT1-MMP transduces intracellular signaling leading to RhoA-mediated CD44 shedding. Treatment of glioma cells with the Rho-kinase (ROK) inhibitor Y27632, or with EGCg, a green tea catechin with anti-MMP and anti-angiogenesis activities, antagonized both RhoA- and MT1-MMP-induced CD44 shedding. Conversely, overexpression of recombinant ROK stimulated CD44 release. Taken together, our results suggest that RhoA/ROK intracellular signaling regulates MT1-MMP-mediated CD44 recognition of HA. These molecular processes may partly explain the diffuse brain-infiltrating character of glioma cells within the surrounding parenchyma and thus be a target for new approaches to anti-tumor therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / pathology
  • Brain Neoplasms / physiopathology
  • Catechin / analogs & derivatives*
  • Catechin / pharmacology
  • Cell Adhesion / drug effects
  • Cell Line, Tumor
  • Cell Membrane / metabolism*
  • Cell Movement
  • Glioma / metabolism*
  • Glioma / pathology
  • Glioma / physiopathology
  • Humans
  • Hyaluronan Receptors / metabolism*
  • Hyaluronic Acid / metabolism
  • Intracellular Signaling Peptides and Proteins
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases / antagonists & inhibitors
  • Metalloendopeptidases / genetics
  • Metalloendopeptidases / metabolism
  • Neoplasm Invasiveness
  • Protein-Serine-Threonine Kinases / metabolism*
  • Recombinant Proteins / metabolism
  • Signal Transduction
  • Transfection
  • rho-Associated Kinases
  • rhoA GTP-Binding Protein / genetics
  • rhoA GTP-Binding Protein / metabolism*

Substances

  • Hyaluronan Receptors
  • Intracellular Signaling Peptides and Proteins
  • Recombinant Proteins
  • Catechin
  • Hyaluronic Acid
  • epigallocatechin gallate
  • Protein-Serine-Threonine Kinases
  • rho-Associated Kinases
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases
  • rhoA GTP-Binding Protein