The p75NTR tumor suppressor induces cell cycle arrest facilitating caspase mediated apoptosis in prostate tumor cells

The p75 neurotrophin receptor (p75NTR) is a death receptor which belongs to the tumor necrosis factor receptor super-family of membrane proteins. This study shows that p75NTR retarded cell cycle progression by induced accumulation of cells in G0/G1 and a reduction in the S phase of the cell cycle. The rescue of tumor cells from cell cycle progression by a death domain deleted (ΔDD) dominant-negative antagonist of p75NTR showed that the death domain transduced anti-proliferative activity in a ligand-independent manner. Conversely, addition of NGF ligand rescued retardation of cell cycle progression with commensurate changes in components of the cyclin/cdk holoenzyme complex. In the absence of ligand, p75NTR-dependent cell cycle arrest facilitated an increase in apoptotic nuclear fragmentation of the prostate cancer cells. Apoptosis of p75NTR expressing cells occurred via the intrinsic mitochondrial pathway leading to a sequential caspase-9 and -7 cascade. Since the death domain deleted dominant-negative antagonist of p75NTR rescued intrinsic caspase associated apoptosis in PC-3 cells, this shows p75NTR was integral to ligand independent induction of apoptosis. Moreover, the ability of ligand to ameliorate the p75NTR-dependent intrinsic apoptotic cascade indicates that NGF functioned as a survival factor for p75NTR expressing prostate cancer cells.