Extracellular cleavage of the p75 neurotrophin receptor is implicated in its pro-survival effect in breast cancer cells

Abstract

The p75 neurotrophin receptor (p75NTR) undergoes sequential proteolytic cleavages leading to the generation of a carboxyl-terminal fragment (p75NTR-CTF) and an intracellular domain (p75NTR-ICD) in many cellular models. We have previously shown that p75NTR is involved in the survival of breast cancer cells. Here, we demonstrated that p75NTR cleavage occurs also in these cells. Surprisingly, p75NTR-CTF increased cell survival, whereas p75NTR-ICD had no effect. The pro-survival effect of p75NTR-CTF was associated with a decrease of TNF-related apoptosis-inducing ligand (TRAIL)-induced PARP and caspase 3 cleavages. Finally, our findings indicate that p75NTR could favor cell survival via its carboxyl-terminal fragment, independently of PI3-kinase, NF-κB, or MAP kinase signaling pathways.

Keywords: ADAM; Breast cancer cell; CTF; FBS; ICD; PS; RIP; Regulated proteolysis; Survival; TAPI; TNF-related apoptosis-inducing ligand; TRAIL; a disintegrin and metalloprotease; carboxyl-terminal fragment; fetal bovine serum; intracellular domain; p75(NTR); presenilin; regulated intramembrane proteolysis; tumor necrosis factor-α protease inhibitor.