Uridine Promotes Bortezomib Resistance in Multiple Myeloma by Upregulating COX5B
10.13865/j.cnki.cjbmb.2025.04.1530
- VernacularTitle:尿苷通过上调COX5B促进多发性骨髓瘤对硼替佐米耐药
- Author:
Lin-Chuang JIA
1
;
Zhi-Qiang LIU
Author Information
1. 天津医科大学基础医学院生理学与病理生理学系,天津 300070
- Publication Type:Journal Article
- Keywords:
multiple myeloma(MM);
bortezomib resistance;
uridine;
mitochondrial oxidative phospho-rylation;
cytochrome C oxidase(COX)
- From:
Chinese Journal of Biochemistry and Molecular Biology
2025;41(6):798-806
- CountryChina
- Language:Chinese
-
Abstract:
Acquired resistance to the proteasome inhibitor bortezomib(BTZ)poses a significant chal-lenge in the treatment of multiple myeloma(MM).During the acquisition of BTZ resistance,metabolic reprogramming is actively engaged in MM cells.However,the key regulatory genes and molecular mecha-nisms mediating bortezomib resistance through this metabolic rewiring have not been fully elucidated.This study aims to investigate the regulatory role of pyrimidine metabolites in drug resistance of MM and their underlying molecular mechanisms.Screening via CCK-8 assays demonstrated that the pyrimidine metabolite uridine is associated with BTZ resistance in MM(P＜0.05).In vitro experiments,including CCK-8 assays,Western blotting,and flow cytometry,demonstrated that uridine partially suppresses bort-ezomib-induced apoptosis in MM cells(P＜0.05).In vivo,experiments utilizing Vk*MYC mouse mod-els,subcutaneous tumor models,and intramedullary bone marrow transplantation models showed that the combination of BTZ and uridine significantly accelerated tumor growth,exacerbated bone destruction,and increased tumor cell infiltration in tumor-bearing mice(P＜0.05).RNA sequencing analysis re-vealed that uridine primarily affects mitochondrial translation in MM at the transcriptional level.Seahorse energy metabolism assays demonstrated that uridine enhances mitochondrial oxidative phosphorylation without significantly altering glycolysis.Transcriptomic analysis further identified a significant upregula-tion of cytochrome c oxidase subunit 5B(COX5B)transcription in uridine-treated groups(P＜0.05).Functional studies confirmed that COX5B is a key molecule mediating uridine's effects on mitochondrial function in MM cells.In conclusion,uridine promotes BTZ resistance in MM by upregulating COX5B transcription and protein expression,thereby enhancing cytochrome c oxidase activity and regulating mito-chondrial oxidative phosphorylation.This study delineates the role of uridine in the development of borte-zomib resistance in MM and elucidates its COX5B-mediated metabolic reprogramming mechanism,provi-ding a theoretical foundation for developing targeted therapies against relapsed/refractory MM.
