Background: 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.
Methods: 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.
Results: 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).
Conclusions: BDNF/TrkB enhanced downstream pathway expression of phosphorylation STAT3 and BRINP3 molecules, promoting RPMI 8226/BTZ cell proliferation and survival.
General significance: These data place BDNF/TrkB at the top of a pSTAT3-BRINP3 survival pathway and link adaptability to BTZ resistant conditions in MM disease.
Keywords: BDNF; BRINP3; Bortezomib resistance; Multiple myeloma; TrkB.
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