Key Laboratory for Molecular Biology and Biopharmaceutics, School of Life Science and Technology, Mianyang Normal University, China.
Department of Endodontics, Stomatological Hospital of Chongqing Medical University, China.
FEBS Open Bio. 2021 Jan;11(1):226-236. doi: 10.1002/2211-5463.13047. Epub 2020 Dec 16.
The p75 neurotrophin receptor (p75 ), 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 and its proteolytic fragments in tumorigenesis remain incompletely understood. Here, we report that the proportion of the p75 carboxyl-terminal fragment (p75 -CTF) is much higher than that of the full-length p75 (p75 -FL) in melanoma cells. Whereas p75 -FL positively regulates apoptosis, p75 -CTF promotes cell proliferation and survival, as well as increasing sorafenib resistance in vivo and in vitro. Moreover, p75 -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, p75 -FL inhibits these processes. Taken together, these findings demonstrate that p75 -CTF and p75 -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 p75 proteolytic fragments may affect biological outcomes in tumor cells.
p75 神经生长因子受体（p75）是肿瘤坏死因子超家族受体的成员，对蛋白水解敏感，并且在各种癌症中均有表达。然而，p75 及其蛋白水解片段在肿瘤发生中的作用仍不完全清楚。在这里，我们报告在黑素瘤细胞中，p75 羧基末端片段（p75-CTF）的比例远高于全长 p75（p75-FL）。虽然 p75-FL 正向调节细胞凋亡，但 p75-CTF 促进细胞增殖和存活，并增加体内和体外索拉非尼耐药性。此外，p75-CTF 激活核因子 κB 通路，并增强其下游基因 c-IAP1/2、FLIP、bFGF、IL8 和 VEGF 的 mRNA 和蛋白水平。相反，p75-FL 抑制这些过程。总之，这些发现表明 p75-CTF 和 p75-FL 在黑素瘤细胞中具有相反的功能，表明这两种蛋白质的比例影响细胞死亡和存活之间的平衡。不同的 p75 蛋白水解片段的存在可能会影响肿瘤细胞中的生物学结果。
