The mechanism by which the proteasome inhibitor synergizes tumor cells’ to TRAIL-induced apoptosis is elusive. This study shows that the diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemic (CLL) cells are more resistant to TRAIL-induced apoptosis when compared with the EBV-transformed B-cells. The resistance of DLBCL cells to TRAIL-induced apoptosis is partly associated with a higher constitutive ratio of Bcl-2/Bax. Bax protein showed a short-life (half-live < 2 hours) in the B-malignant cells when protein synthesis was inhibited by cycloheximide (CHX). Bax expression varied at the protein but not at the mRNA levels. Bax ubiquitination and degradation occur during the treatment with TRAIL and confer resistance of B-malignant cells to TRAIL-induced apoptosis. The proteasome inhibitor, PS-341 or MG-132, sensitizes TRAIL-induced apoptosis by maintaining levels of the active Bax. The ubiquitin-dependent Bax degradation was also detected in the primary tumor materials of DLBCL and follicular lymphoma (FL) but not in control tonsil tissues. Our data suggest that ubiquitin/proteasome-dependent Bax degradation is one of the mechanisms of resistance to TRAIL-induced apoptosis in B-cell malignancies and it can be prevented by co-treatment with proteasome inhibitor. This study indicates that increased Bax degradation activity may play an important role in tumorigenesis in B-cell malignancies.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA