BDNF/TrkB confers bortezomib resistance in multiple myeloma by inducing BRINP3

The proteasome inhibitor bortezomib (BTZ) has significantly improved the survival of multiple myeloma (MM) patients. However, most MM patients still relapse and have drug resistance after BTZ treatment. siRNA transfection was performed to knock down BDNF and TrkB expression. ELISA, western blot, quantitative polymerase chain reaction, CCK-8 assay, and flow cytometry analysis were performed to analyze the functions of BDNF/TrkB signaling in MM cells. We identified a cell-autonomous mechanism that promotes BTZ resistance in MM, prolongs their RPMI 8226/BTZ resistant cell survival and optimizes their proliferating function. Specifically, RPMI 8226/BTZ cells produced the brain derived neurotrophic factor (BDNF) and its receptor TrkB, which served as a survival factor in the RPMI 8226/BTZ resistant environment. BDNF/TrkB induced phosphorylation of STAT3 that upregulated the bone morphogenetic protein/retinoic acid inducible neural-specific 3 (BRINP3). BDNF/TrkB enhanced downstream pathway expression of phosphorylation STAT3 and BRINP3 molecules, promoting RPMI 8226/BTZ cell proliferation and survival. These data place BDNF/TrkB at the top of a pSTAT3-BRINP3 survival pathway and link adaptability to BTZ resistant conditions in MM disease.