Inhibition of nuclear translocation of nuclear factor-κB despite lack of functional IκBα protein overcomes multiple defects in apoptosis signaling in human B-cell malignancies

Purpose: Defective apoptosis signaling is a typical feature of classic Hodgkin's lymphoma, multiple myeloma, and activated B-cell-like diffuse large B-cell lymphoma. In these malignancies, the transcription factor nuclear factor-kappa B (NF-kappa B) is a critical mediator of apoptosis resistance and oncogenic growth, making it an attractive therapeutic target. Here, we sought to determine how to overcome apoptosis resistance experimentally in these malignancies by targeting NF-kappa B. Experimental Design: We investigated the effect of different inhibitors of NF-kappa B on classic Hodgkin's lymphoma, multiple myeloma, and activated B-cell-like diffuse large B-cell lymphoma cell lines harboring different molecular defects in apoptosis signaling both quantitatively and qualitatively. Results: The cyclopentenone prostaglandin, 15-deoxy-Delta 12,14-prostaglandin J(2), a known inhibitor of NF-kappa B, induced caspase-dependent apoptosis; it restored mitochondrial apoptotic signaling by down-regulation of X-linked inhibitor of apoptosis protein and heat shock protein 27 and led to breakdown of the mitochondrial membrane potential and, finally, cleavage of caspase-3 irrespective of I kappa B alpha mutational status. Surprisingly, 15-deoxy-Delta 12,14-prostaglandin J2 and the I kappa B kinase inhibitor curcumin both reduced nuclear levels of p65 in cell lines lacking I kappa B alpha, suggesting that inhibition of nuclear translocation of NF-kappa B can occur in the absence of I kappa B alpha. Finally, a synthetic peptide that specifically abrogates the assembly of the I kappa B kinase complex killed I kappa B alpha-defective cells by induction of apoptosis, paralleled by reduction of nuclear NF-kappa B. Conclusions: These results show that molecular defects in apoptotic signaling, such as I kappa B alpha mutations, can be circumvented by targeting NF-kappa B through inhibition of the I kappa B kinase complex followed by induction of apoptosis in classic Hodgkin's lymphoma, multiple myeloma, and activated B-cell-like diffuse large B-cell lymphoma. Thus, targeting I kappa B kinases may represent an attractive therapeutic approach against these malignancies regardless of the mutational status Of I kappa B alpha.