Inhibition of Necl-5 (CD155/PVR) reduces glioblastoma dispersal and decreases MMP-2 expression and activity

J Neurooncol. 2011 Apr;102(2):225-35. doi: 10.1007/s11060-010-0323-5. Epub 2010 Aug 3.

Abstract

Patients afflicted with glioblastoma (GBM) have poor survival due to dispersive invasion throughout the brain. Necl-5, a cell surface receptor for vitronectin, is expressed in GBM but not normal brain. In several GBM cell lines Necl-5 promotes migration and invasion but the mechanism is poorly understood. In this study, we show that knockdown of Necl-5 by RNAi results in markedly decreased invasion of A172 GBM cells in a 3-dimensional matrix. There is a concomitant decrease in the expression and activity of matrix metalloproteinase-2 (MMP-2), a known factor in GBM invasion and disease severity. Knockdown of Necl-5 diminishes basal activation of Akt, an established mediator of MMP-2 expression in gliomas. Knockdown of Necl-5 also limits the maximal Akt activation in response to vitronectin, which requires the activity of Integrin-linked kinase (ILK). During migration, Necl-5, Akt and ILK co-localize at focal contacts at the leading edge of the plasma membrane, suggesting that these molecules may act to integrate Akt signaling at the leading edge to induce MMP-2 expression. By virtue of its restricted expression in GBM and its role in invasion, Necl-5 may be an attractive target for limiting MMP-2 production in glioblastoma, and therefore limiting dispersal.

Publication types

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

MeSH terms

  • Blotting, Western
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / prevention & control
  • Cell Membrane
  • Cell Movement
  • Culture Media, Conditioned / pharmacology
  • Glioblastoma / metabolism*
  • Glioblastoma / prevention & control
  • Humans
  • Immunoenzyme Techniques
  • Matrix Metalloproteinase 2 / genetics
  • Matrix Metalloproteinase 2 / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Messenger / genetics
  • RNA, Small Interfering / pharmacology
  • Receptors, Virus / antagonists & inhibitors*
  • Receptors, Virus / genetics
  • Receptors, Virus / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Tumor Cells, Cultured
  • Wound Healing

Substances

  • Culture Media, Conditioned
  • RNA, Messenger
  • RNA, Small Interfering
  • Receptors, Virus
  • poliovirus receptor
  • integrin-linked kinase
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Matrix Metalloproteinase 2