Inhibition of the ubiquitin-proteasome system sensitizes TRAIL-resistant prostate cancer cells by up-regulation of death receptor 5

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a type II transmembrane cytokine and a potent inducer of apoptosis in cancer cells. However, some cancer cells, particularly prostate cancer cells, such as LNCaP cells, were found to be resistant to TRAIL. In the present study, we demonstrate that the proteasome inhibitor ALLN significantly enhanced TRAIL-induced apoptosis by up-regulating TRAIL/Apo2L death receptor 5 expression in LNCaP cells. LNCaP cells were exposed to ALLN for 3 h and treated with recombinant TRAIL protein. ALLN alone induced a 20% cell death after a 3--h treatment; however, pretreatment with ALLN induced death to more than 80% of cells after 3 h of TRAIL treatment. ALLN also enhanced the cell death of TRAIL-sensitive/resistant prostate cancer and other cancer cell lines. Western blotting results showed that the combination of ALLN and TRAIL increased the levels of activated caspase-8, -3 and DR-5 in LNCaP cells. Furthermore, we observed an increase in DR-5 expression following 3 h of treatment of ALLN alone. Taken together, our findings indicate that ALLN enhances TRAIL-induced apoptosis in LNCaP cells by up-regulating DR-5 expression. Thus, our results suggest that the combination of ALLN and TRAIL is a novel therapeutic strategy in TRAIL-resistant tumors.