The mechanism for netrin-1 regulated anti-cell death activity and its role in human diseases

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In the present study, we identified a novel netrin-1 receptor X that mediates netrin-1 regulated anti-cell death activity. The interaction of netrin-1 with receptor X not only blocked p53-dependent apoptosis but also induced chemotaxis of both vascular endothelial cells and cancer cells. The interaction led to activation of AKT and Src. In vivo, netrin-1 was colocalized with receptor X at the basement membrane of colorectal epithelial cells. Netrin-1 expression was frequently lost in human colorectal cancer tissues whereas the expression was elevated in cancer stromal region. In 3D culture experiment, the interaction of netrin-1 with receptor X induced cell polarization and growth suppression of colorectal cancer cells. These results suggest that the signaling pathway via netrin-1 and receptor X plays a critical role in cell polarity to suppress tumor initiation and progression.