The p75 neurotrophin receptor (p75 NTR), 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 p75 NTR and its proteolytic fragments in tumorigenesis remain incompletely understood. Here, we report that the proportion of the p75 NTR carboxyl-terminal fragment (p75 NTR-CTF) is much higher than that of the full-length p75 NTR (p75 NTR-FL) in melanoma cells. While p75 NTR-FL positively regulates apoptosis, p75 NTR-CTF promotes cell proliferation and survival as well as increasing sorafenib resistance in vivo and in vitro. Moreover, p75 NTR-CTF activates the NF-κB pathway and enhances the mRNA and protein levels of its downstream genes c-IAP1/2, FLIP, bFGF, IL8 and VEGF. On the contrary, p75 NTR-FL inhibits these processes. Taken together, these findings demonstrate that p75 NTR-CTF and p75 NTR-FL have opposing
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