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

摘要

The p75 neurotrophin receptor (p75supNTR/sup), 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 p75supNTR/sup and its proteolytic fragments in tumorigenesis remain incompletely understood. Here, we report that the proportion of the p75supNTR/sup carboxyl‐terminal fragment (p75supNTR/sup‐CTF) is much higher than that of the full‐length p75supNTR/sup (p75supNTR/sup‐FL) in melanoma cells. Whereas p75supNTR/sup‐FL positively regulates apoptosis, p75supNTR/sup‐CTF promotes cell proliferation and survival, as well as increasing sorafenib resistance in vivo and in vitro . Moreover, p75supNTR/sup‐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, p75supNTR/sup‐FL inhibits these processes. Taken together, these findings demonstrate that p75supNTR/sup‐CTF and p75supNTR/sup‐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 p75supNTR/sup proteolytic fragments may affect biological outcomes in tumor cells.