The p75NTR and its carboxyl-terminal fragment exert opposing effects on melanoma cell proliferation and apoptosis via modulation of the NF-κB pathway

Abstract

The p75 neurotrophin receptor (p75NTR), a member of the tumor necrosis factor superfamily of receptors, is sensitive to proteolysis and has been observed to be expressed in various cancers. However, the roles of p75NTR and its proteolytic fragments in tumorigenesis remain incompletely understood. Here, we report that the proportion of the p75NTR carboxyl-terminal fragment (p75NTR-CTF) is much higher than that of the full-length p75NTR (p75NTR-FL) in melanoma cells. Whereas p75NTR-FL positively regulates apoptosis, p75NTR-CTF promotes cell proliferation and survival, as well as increasing sorafenib resistance in vivo and in vitro. Moreover, p75NTR-CTF activates the nuclear factor kappa B pathway and enhances the mRNA and protein levels of its downstream genes c-IAP1/2, FLIP, bFGF, IL8 and VEGF. On the contrary, p75NTR-FL inhibits these processes. Taken together, these findings demonstrate that p75NTR-CTF and p75NTR-FL have opposing functions in melanoma cells, suggesting that the ratio of the two proteins affects the balance between cell death and survival. The presence of distinct p75NTR proteolytic fragments may affect biological outcomes in tumor cells.