Structural Decoding of the Netrin-1/UNC5 Interaction and its Therapeutical Implications in Cancers

Cancer Cell. 2016 Feb 8;29(2):173-85. doi: 10.1016/j.ccell.2016.01.001.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Humans
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Neoplasms / therapy*
  • Nerve Growth Factors / immunology
  • Nerve Growth Factors / metabolism*
  • Netrin Receptors
  • Netrin-1
  • Protein Binding
  • Receptors, Cell Surface / metabolism*
  • Tumor Suppressor Proteins / immunology
  • Tumor Suppressor Proteins / metabolism*

Substances

  • NTN1 protein, human
  • Nerve Growth Factors
  • Netrin Receptors
  • Ntn1 protein, mouse
  • Receptors, Cell Surface
  • Tumor Suppressor Proteins
  • UNC5C protein, human
  • Netrin-1