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

作者：Li Bao, Yutong Wang, Minqiu Lu, Lei Shi, Bin Chu, Shan Gao · 发表于：Biochimica et Biophysica Acta (BBA) - General Subjects · 年份：2022 · DOI：10.1016/j.bbagen.2022.130299 · 被引用次数：3 · 研究领域：Multiple Myeloma Research and Treatments、Ubiquitin and proteasome pathways、Protein Degradation and Inhibitors

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.