Bortezomib inhibits proteasomal degradation of IκBα and induces mitochondrial dependent apoptosis in activated B-cell diffuse large B-cell lymphoma

Activated B-cell type lymphoma (ABC), a subgroup of diffuse large B-cell lymphoma (DLBCL), has a worse survival after upfront chemotherapy and is characterized by constitutive activation of the anti-apoptotic nuclear factor-kappa B (NF kappa B) pathway. The implication of NF kappa B inhibition in ABC has not yet been fully explored as a potential therapeutic target. Therefore, a panel of ABC cell lines was used to examine the effect of bortezomib, a proteasome inhibitor which blocks degradation of I kappa B alpha and consequently inhibits NF kappa B activity. Our data showed that bortezomib caused a dose-dependent growth inhibition and induction of apoptosis in all cell lines studied. We next determined the status of the NF kappa B pathway following bortezomib treatment and found that there was accumulation of I kappa B alpha without affecting its phosphorylation status at an early time point. Electrophoretic mobility shift assay showed that bortezomib treatment inhibited constitutive nuclear NF kappa B in ABC cell lines. Furthermore, treatment of ABC cell lines with bortezomib for 48 h also down-regulated the expression of NF kappa B-regulated gene products, such as I kappa B alpha, Bcl-2, Bcl-Xl, XIAP and survivin, leading to apoptosis via the mitochondrial apoptotic pathway. Altogether, these results suggest that NF kappa B may be a potential target for therapeutic intervention in DLBCL using proteasomal inhibitors such as bortezomib.