Netrin-1 was recently proposed to control
tumorigenesis by inhibiting apoptosis induced by the dependence receptors DCC (Deleted in
colorectal cancer) and UNC5H. Although the loss of these dependence receptors' expression has been described as a selective advantage for
tumor growth and progression in numerous
cancers, recent observations have shown that some
tumors may use an alternative strategy to block dependence receptor-induced programmed cell death: the autocrine expression of
netrin-1. This alternative strategy has been observed in a large fraction of aggressive breast
cancers,
neuroblastoma, pancreatic
adenocarcinoma, and
lung cancer. This observation is of potential interest regarding future targeted
therapy, as in such cases interfering with the ability of
netrin-1 to inhibit DCC or UNC5H-induced cell death is associated with apoptosis of netrin-1-expressing
tumor cells in vitro, and with inhibition of
tumor growth or
metastasis in different animal
tumor models. The understanding of the mechanism by which
netrin-1 inhibits cell death is therefore of interest. Here, we show that
netrin-1 triggers the multimerization of both DCC and UNC5H2 receptors, and that multimerization of the intracellular domain of DCC and UNC5H2 is the critical step to inhibit the proapoptotic effects of both of these receptors. Taking advantage of this property, we utilized a recombinant specific domain of DCC that (i) interacts with
netrin-1 and (ii) inhibits netrin-1-induced multimerization, to trigger apoptosis in
netrin-dependent
tumor cells.