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Structural decoding of the netrin-1/UNC5 interaction and its therapeutical implications in cancers

Item Type:Article
Title:Structural decoding of the netrin-1/UNC5 interaction and its therapeutical implications in cancers
Creators Name:Grandin, M. and Meier, M. and Delcros, J.G. and Nikodemus, D. and Reuten, R. and Patel, T.R. and Goldschneider, D. and Orriss, G. and Krahn, N. and Boussouar, A. and Abes, R. and Dean, Y. and Neves, D. and Bernet, A. and Depil, S. and Schneiders, F. and Poole, K. and Dante, R. and Koch, M. and Mehlen, P. and Stetefeld, J.
Abstract:Netrin-1 has been shown to be up-regulated in a fraction of human cancers as a mechanism to allow these tumors to escape the pro-apoptotic activity of some of its main dependence receptors, the UNC5 homologs (UNC5H). Here we identify the V-2 domain of netrin-1 to be important for its interaction with the Ig1/Ig2 domains of UNC5H2. We generate a humanized anti-netrin-1 antibody that disrupts the interaction between netrin-1 and UNC5H2 and triggers death of netrin-1-expressing tumor cells in vitro. We also present evidence that combining the anti-netrin-1 antibody with epidrugs such as decitabine could be effective in treating tumors showing no or modest netrin-1 expression. These results support that this antibody is a promising drug candidate.
Keywords:Cell Surface Receptors, Molecular Models, Neoplasms, Nerve Growth Factors, Nude Mice, Protein Binding, Tumor Suppressor Proteins, Animals, Mice
Source:Cancer Cell
Publisher:Cell Press / Elsevier
Page Range:173-185
Date:8 February 2016
Official Publication:https://doi.org/10.1016/j.ccell.2016.01.001
PubMed:View item in PubMed

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