Critical roles of Noxa and Mcl-1 in the signaling mechanisms of bortezomib in TRAF3-deficient mouse B lymphoma and human multiple myeloma cells

Bortezomib, a clinical drug for multiple myeloma (MM) and mantle cell lymphoma, exhibits complex signaling mechanisms, which vary depending on the cancer cell type and the critical genetic alterations of each cancer. In the present study, we investigated the signaling mechanisms of bortezomib in mouse B lymphoma and human MM cells deficient in a new tumor suppressor gene, TRAF3. We found that bortezomib robustly induced up-regulation of the pro-apoptotic protein Noxa, cleavage of the anti-apoptotic protein Mcl-1, and accumulation of the oncoprotein c-Myc. Interestingly, bortezomib exhibited contrasting roles on canonical versus non-canonical NF-kB pathways. Overexpression of Noxa was sufficient to induce apoptosis and inhibit proliferation in human MM cells by inducing cleavage of Mcl-1 and caspase 3. Furthermore, we demonstrated that oridonin (an inhibitor of NF-kB1 and NF-kB2) or AD 198 (a drug targeting c-Myc) drastically potentiated the anti-cancer effects of bortezomib in TRAF3-deficient malignant B cells. Taken together, our findings provide new insights into the signaling mechanisms of bortezomib, which would aid the design of novel bortezomib-based combination therapies. Our results also provide a rationale for clinical evaluation of the combinations of bortezomib and oridonin (or other inhibitors of NF-kB1/2) or AD 198 (or other drugs targeting c-Myc) in the treatment of lymphoma and MM, especially in patients containing TRAF3 deletions or relevant mutations.