Overcoming Resistance of Prostate Cancer to TRAIL - Mediated Apoptosis

摘要

Purpose-TRAIL (TNF-related apoptosis inducing ligand) is a protein that induces apoptotic cell death by activating a cascade of cell death caspases. TRAIL is a potential candidate for treatment of prostate cancer. However, it is clear that the majority of prostate cancer cell lines are either insensitive or only partially sensitive to this agent. The purpose of this proposal is to understand the nature of the resistance to this agent and to develop biochemical mechanisms to overcome this inhibition of cell death. Scope: This proposal focuses on TRAIL resistant human prostate cancer cell lines including LNCaP, PC-3 and DU-145. Major Findings: We find that TRAIL induced cell death can be markedly enhanced by the proteasome inhibitor PS-341. The mechanism of action of PS-341 includes increases in the TRAIL receptor, and increases in the BH3 proteins, Bik and Bim. This combination kills cells in the presence Bcl-xL and the absence of Bax but appears to require the Bak protein for activity. Results and Significance: This result suggest that this combination of agents will have significant activity in the clinic. It also suggests that changes in the level of the TRAIL receptor, Dr5, and the protein Bik can be markers of the mechanism of actions of PS-341.