Signaling mechanisms of bortezomib in TRAF3-deficient mouse B lymphoma and human multiple myeloma cells.

Abstract

Bortezomib, a clinical drug for multiple myeloma (MM) and mantle cell lymphoma, exhibits complex mechanisms of action, which vary depending on the cancer type and the critical genetic alterations of each cancer. Here 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 consistently induced up-regulation of the cell cycle inhibitor p21(WAF1) and the pro-apoptotic protein Noxa as well as cleavage of the anti-apoptotic protein Mcl-1. Interestingly, bortezomib induced the activation of NF-κB1 and the accumulation of the oncoprotein c-Myc, but inhibited the activation of NF-κB2. Furthermore, we demonstrated that oridonin (an inhibitor of NF-κB1 and NF-κB2) 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 increase the understanding of the mechanisms of action 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-κB1/2) 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.

• Authors: Shanique K E Edwards, Yeming Han, Yingying Liu, Benjamin Z Kreider, Yan Liu, Sukhdeep Grewal, Anand Desai, Jacqueline Baron, Carissa R Moore, Chang Luo, Ping Xie
• Journal: Leukemia research (Leuk Res) Vol. 41 Pg. 85-95 (Feb 2016) ISSN: 1873-5835 [Electronic] England
• PMID: 26740054 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Proteasome Inhibitors
• TNF Receptor-Associated Factor 3
• Bortezomib

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Bortezomib (pharmacology)
• Disease Models, Animal
• Humans
• Immunoblotting
• Immunoprecipitation
• Lymphoma, B-Cell (genetics)
• Mice
• Multiple Myeloma (genetics)
• Proteasome Inhibitors (pharmacology)
• Signal Transduction (drug effects)
• TNF Receptor-Associated Factor 3 (deficiency, genetics)
• Transduction, Genetic