Inhibition of Necl-5 (CD155/PVR) reduces glioblastoma dispersal and decreases MMP-2 expression and activity |
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Authors: | Brian M Enloe Daniel G Jay |
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Institution: | (1) Tufts University School of Medicine, Boston, MA, USA; |
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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. |
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