Inhibition of Necl-5 (CD155/PVR) reduces glioblastoma dispersal and decreases MMP-2 expression and activity.
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.
Enloe
Brian M
BM
Tufts University School of Medicine, Boston, MA, USA.
Jay
Daniel G
DG
D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism* / Q000517:prevention & control; D002462:Cell Membrane; D002465:Cell Movement; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005909:Glioblastoma / Q000378:metabolism* / Q000517:prevention & control; D006801:Humans; D007124:Immunoenzyme Techniques; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D011991:Receptors, Virus / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014945:Wound Healing; D000099200:Scaffold Protein ILK
D017077:Culture Media, Conditioned; D020778:Matrix Metalloproteinase 2; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011991:Receptors, Virus; D000099200:Scaffold Protein ILK; C066100:poliovirus receptor