title: 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.affiliation: Department of Cell Biology and Neuroscience, Piscataway, NJ 08854, United States; Graduate Program in Molecular Biosciences, Rutgers University, Piscataway, NJ 08854, United States.
authors.forename: Shanique K E
authors.initials: SK
authors.lastname: Edwards
authors.affiliation: Department of Cell Biology and Neuroscience, Piscataway, NJ 08854, United States.
authors.forename: Yeming
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Cell Biology and Neuroscience, Piscataway, NJ 08854, United States.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Cell Biology and Neuroscience, Piscataway, NJ 08854, United States.
authors.forename: Benjamin Z
authors.initials: BZ
authors.lastname: Kreider
authors.affiliation: Department of Cell Biology and Neuroscience, Piscataway, NJ 08854, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Cell Biology and Neuroscience, Piscataway, NJ 08854, United States.
authors.forename: Sukhdeep
authors.initials: S
authors.lastname: Grewal
authors.affiliation: Department of Cell Biology and Neuroscience, Piscataway, NJ 08854, United States.
authors.forename: Anand
authors.initials: A
authors.lastname: Desai
authors.affiliation: Department of Cell Biology and Neuroscience, Piscataway, NJ 08854, United States.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Baron
authors.affiliation: Department of Cell Biology and Neuroscience, Piscataway, NJ 08854, United States.
authors.forename: Carissa R
authors.initials: CR
authors.lastname: Moore
authors.affiliation: Department of Cell Biology and Neuroscience, Piscataway, NJ 08854, United States.
authors.forename: Chang
authors.initials: C
authors.lastname: Luo
authors.affiliation: Department of Cell Biology and Neuroscience, Piscataway, NJ 08854, United States; Member, Rutgers Cancer Institute of New Jersey, United States. Electronic address: xiep@rci.rutgers.edu.
authors.forename: Ping
authors.initials: P
authors.lastname: Xie
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000069286:Bortezomib / Q000494:pharmacology*; D004195:Disease Models, Animal; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D016393:Lymphoma, B-Cell / Q000235:genetics*; D051379:Mice; D009101:Multiple Myeloma / Q000235:genetics*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D048008:TNF Receptor-Associated Factor 3 / Q000172:deficiency* / Q000235:genetics; D014161:Transduction, Genetic
chemical_list: D000970:Antineoplastic Agents; D061988:Proteasome Inhibitors; D048008:TNF Receptor-Associated Factor 3; D000069286:Bortezomib
keywords: AD 198; B lymphoma; Bortezomib; Multiple myeloma; Noxa; Oridonin; TRAF3