The p75(NTR) tumor suppressor induces cell cycle arrest facilitating caspase mediated apoptosis in prostate tumor
Fatima Khwaja1, Arshia Tabassum, Jeff Allen
1Department of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC 20057-1436, USA.
Abstract:
The p75 neurotrophin receptor (p75(NTR)) is a death receptor which belongs to the tumor necrosis factor receptor super-family of membrane proteins. This study shows that p75(NTR) 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 (DeltaDD) dominant-negative antagonist of p75(NTR) 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, p75(NTR)-dependent cell cycle arrest facilitated an increase in apoptotic nuclear fragmentation of the prostate cancer cells. Apoptosis of p75(NTR) 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 p75(NTR) rescued intrinsic caspase associated apoptosis in PC-3 cells, this shows p75(NTR) was integral to ligand independent induction of apoptosis. Moreover, the ability of ligand to ameliorate the p75(NTR)-dependent intrinsic apoptotic cascade indicates that NGF functioned as a survival factor for p75(NTR) expressing prostate cancer cells.
Insights
The p75 neurotrophin receptor (p75(NTR)) halts prostate cancer cell proliferation and induces apoptosis. Nerve growth factor (NGF) acts as a survival factor, counteracting p75(NTR)
Area of Science:
- Molecular biology
- Cell biology
- Cancer research
Background:
- The p75 neurotrophin receptor (p75(NTR)) is a member of the tumor necrosis factor receptor superfamily.
- p75(NTR) functions as a death receptor, influencing cell fate.
Purpose of the Study:
- To investigate the role of p75(NTR) in prostate cancer cell cycle progression and apoptosis.
- To elucidate the mechanisms of p75(NTR)-mediated anti-proliferative and pro-apoptotic activities.
Main Methods:
- Cell cycle analysis using flow cytometry.
- Dominant-negative antagonist (DeltaDD) to inhibit p75(NTR) function.
- Assessment of apoptosis via nuclear fragmentation and caspase activation.
- Treatment with Nerve Growth Factor (NGF) ligand.
Main Results:
- p75(NTR) expression caused cell cycle arrest at G0/G1 and reduced S phase.
- The death domain of p75(NTR) mediated ligand-independent anti-proliferative effects.
- NGF ligand rescued cell cycle progression and modulated cyclin/cdk holoenzyme complex.
- p75(NTR) induced apoptosis via the intrinsic mitochondrial pathway (caspase-9/-7 cascade) in a ligand-independent manner.
- The DeltaDD antagonist blocked p75(NTR)-induced apoptosis, confirming its integral role.
- NGF acted as a survival factor, ameliorating p75(NTR)-dependent apoptosis.
Conclusions:
- p75(NTR) plays a dual role in prostate cancer, inhibiting proliferation and inducing apoptosis.
- The death domain is critical for p75(NTR)'s anti-proliferative and apoptotic functions.
- NGF acts as a survival factor for p75(NTR)-expressing prostate cancer cells, opposing its pro-apoptotic effects.
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