Cell metabolism · 2023
Targeting gut microbial nitrogen recycling and cellular uptake of ammonium to improve bortezomib resistance in multiple myeloma.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Zhu Yinghong, Jian Xingxing, Chen Shuping, An Gang, Jiang Duanfeng, Yang Qin, Zhang Jingyu, Hu Jian, Qiu Yi, Feng Xiangling, Guo Jiaojiao, Chen Xun, Li Zhengjiang, Zhou Ruiqi, Hu Cong, He Nihan, Shi Fangming, Huang Siqing, Liu Hong, Li Xin, Xie Lu, Zhu Yan, Zhao Lia, Jiang Yichuan, Li Jian, Wang Jinuo, Qiu Lugui, Chen Xiang, Jia Wei, He Yanjuan, Zhou Wen
Аннотация
The gut microbiome has been found to play a crucial role in the treatment of multiple myeloma (MM), which is still considered incurable due to drug resistance. In previous studies, we demonstrated that intestinal nitrogen-recycling bacteria are enriched in patients with MM. However, their role in MM relapse remains unclear. This study highlights the specific enrichment of Citrobacter freundii (C. freundii) in patients with relapsed MM. Through fecal microbial transplantation experiments, we demonstrate that C. freundii plays a critical role in inducing drug resistance in MM by increasing levels of circulating ammonium. The ammonium enters MM cells through the transmembrane channel protein SLC12A2, promoting chromosomal instability and drug resistance by stabilizing the NEK2 protein. We show that furosemide sodium, a loop diuretic, downregulates SLC12A2, thereby inhibiting ammonium uptake by MM cells and improving progression-free survival and curative effect scores. These findings provide new therapeutic targets and strategies for the intervention of MM progression and drug resistance.