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

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Item Type:	Article
Title:	Structural decoding of the netrin-1/UNC5 interaction and its therapeutical implications in cancers
Creators Name:	Grandin, M., Meier, M., Delcros, J.G., Nikodemus, D., Reuten, R., Patel, T.R., Goldschneider, D., Orriss, G., Krahn, N., Boussouar, A., Abes, R., Dean, Y., Neves, D., Bernet, A., Depil, S., Schneiders, F., Poole, K., Dante, R., Koch, M., 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
ISSN:	1535-6108
Publisher:	Cell Press / Elsevier
Volume:	29
Number:	2
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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