Zaal Esther A, de Grooth Harm-Jan, Oudaert Inge, Langerhorst Pieter, Levantovsky Sophie, van Slobbe Gijs J J, Jansen Jeroen W A, Menu Eline, Wu Wei, Berkers Celia R
Biomolecular Mass Spectrometry and Proteomics, Bijvoet Centre for Biomolecular Research and Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
Division of Cell Biology, Metabolism & Cancer, Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Mol Omics. 2022 Jan 17;18(1):19-30. doi: 10.1039/d1mo00106j.
During the development of drug resistance, multiple myeloma (MM) cells undergo changes to their metabolism. However, how these metabolic changes can be exploited to improve treatment efficacy is not known. Here we demonstrate that targeting coenzyme Q10 (CoQ) biosynthesis through the mevalonate pathway works in synergy with the proteasome inhibitor bortezomib (BTZ) in MM. We show that gene expression signatures relating to the mitochondrial tricarboxylic acid (TCA) cycle and electron transport chain (ETC) predispose to clinical BTZ resistance and poor prognosis in MM patients. Mechanistically, BTZ-resistant cells show increased activity of glutamine-driven TCA cycle and oxidative phosphorylation, together with an increased vulnerability towards ETC inhibition. Moreover, BTZ resistance is accompanied by high levels of the mitochondrial electron carrier CoQ, while the mevalonate pathway inhibitor simvastatin increases cell death and decreases CoQ levels, specifically in BTZ-resistant cells. Both and , simvastatin enhances the effect of bortezomib treatment. Our study links CoQ synthesis to drug resistance in MM and provides a novel avenue for improving BTZ responses through statin-induced inhibition of mitochondrial metabolism.
在耐药性发展过程中，多发性骨髓瘤（MM）细胞的代谢会发生变化。然而，如何利用这些代谢变化来提高治疗效果尚不清楚。在此，我们证明通过甲羟戊酸途径靶向辅酶Q10（CoQ）生物合成在MM中与蛋白酶体抑制剂硼替佐米（BTZ）协同发挥作用。我们表明，与线粒体三羧酸（TCA）循环和电子传递链（ETC）相关的基因表达特征易导致MM患者临床BTZ耐药和预后不良。从机制上讲，BTZ耐药细胞显示谷氨酰胺驱动的TCA循环和氧化磷酸化活性增加，同时对ETC抑制的敏感性增加。此外，BTZ耐药伴随着线粒体电子载体CoQ的高水平，而甲羟戊酸途径抑制剂辛伐他汀增加细胞死亡并降低CoQ水平，特别是在BTZ耐药细胞中。辛伐他汀和硼替佐米均增强了硼替佐米治疗的效果。我们的研究将CoQ合成与MM中的耐药性联系起来，并为通过他汀类药物诱导的线粒体代谢抑制来改善BTZ反应提供了一条新途径。
