TY - JOUR
T1 - Targeting coenzyme Q10 synthesis overcomes bortezomib resistance in multiple myeloma
AU - Zaal, Esther A.
AU - de Grooth, Harm-Jan
AU - Oudaert, Inge
AU - Langerhorst, Pieter
AU - Levantovsky, Sophie
AU - van Slobbe, Gijs J. J.
AU - Jansen, Jeroen W. A.
AU - Menu, Eline
AU - Wu, Wei
AU - Berkers, Celia R.
N1 - Funding Information: The authors would like to thank Boudewijn Burgering and Maaike Meerlo for their assistance in extracellular flux analysis, Christoph Driessen for BTZ-and CFZ-resistant cell lines, and Albert Heck for constructive discussions. IO was supported by FWO (Vlaanderen), EM by Kom Op Tegen Kanker (Vlaanderen) and the International Myeloma Foundation. Publisher Copyright: This journal is © The Royal Society of Chemistry
PY - 2022/1/1
Y1 - 2022/1/1
N2 - 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 in vitro and in vivo, 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.
AB - 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 in vitro and in vivo, 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85123641587&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/34879122
UR - http://www.scopus.com/inward/record.url?scp=85123641587&partnerID=8YFLogxK
U2 - https://doi.org/10.1039/d1mo00106j
DO - https://doi.org/10.1039/d1mo00106j
M3 - Article
C2 - 34879122
SN - 2515-4184
VL - 18
SP - 19
EP - 30
JO - Molecular omics
JF - Molecular omics
IS - 1
ER -