Activating Cell Death Ligand Signaling Through Proteasome Inhibition

摘要

The purpose of this past year's work was to investigate the in vivo anti-cancer efficacy of combining proteasome inhibition with recombinant human TRAIL protein on prostate cancer. This combined treatment regimen was well tolerated and prevented the growth of prostate tumors in a LNCaP xenograft model. Each agent used singly demonstrated no effect on tumor volume. To elucidate the mechanism of the anti-tumor activity, angiogenesis, proliferation, and apoptosis was examined. No detectable effects on blood vessel density were observed. A wave of caspase-8 activity and tumor cell apoptosis was noted after the initial combined treatments. A decrease in proliferation was discovered only at the later time points. To determine if the activation of caspase-8 was responsible for the reported anti-cancer effect of proteasome inhibition as a single agent, PC3 cells were made deficient in death receptor signaling. The death receptor defective cells were resistant to the anti-cancer effects of Velcade. This study provides a proof-of-principle in animals that proteasome inhibition combined with a death receptor agonist is a viable treatment for human prostate cancer.