Netrin-1 and UNC5H receptors: role in cell fate determination and carcinogenesis

Abstract Dependence receptors are distinctive type of receptors that induce a cellular state of dependence towards ligand availability. UNC5H receptors are notable examples of these receptors. They promote cell survival upon binding to their ligands, including netrin-1, whereas the absence of the ligand induces apoptosis. Unbound UNC5B promotes apoptosis through death-associated protein kinase (DAPK), while cell survival requires ligand binding. Previous studies have also shown the requirement of protein phosphatase 2A (PP2A) for this UNC5B-mediated apoptosis. Netrin-1 and its receptors are involved in nervous development, angiogenesis, and homeostatic maintenance of intestinal epithelium. UNC5H receptors are often down-regulated in various tumors, whereas several cancers have up-regulated netrin-1 expression, and both these conditions promote tumor cell survival. Interestingly, the interaction between netrin-1 and its receptors has been targeted in cancers to promote cancer cell death, reverse epithelial-to-mesenchymal transition, and inhibit metastasis and anti-cancer drug resistance. Here we discuss the mechanisms of signaling through UNC5H receptors and their role in normal cellular physiology and carcinogenesis. Furthermore, in the present review, we highlight the strategies that are currently being tested to target the netrin-UNC5H pathway for the treatment of cancer.