ABSTRACT It is generally accepted that intracellular oxidative stress induced by proteasome inhibitors is a byproduct of endoplasmic reticulum (ER) stress. Here we report a mechanism

underlying the ability of proteasome inhibitors bortezomib (BTZ) and carfilzomib (CFZ) to directly induce oxidative and ER stresses in multiple myeloma (MM) cells via transcriptional

repression of a gene encoding mitochondrial thioredoxin reductase (TXNRD2). TXNRD2 is critical for maintenance of intracellular red–ox status and detoxification of reactive oxygen species.

Depletion of TXNRD2 to the levels detected in BTZ- or CFZ-treated cells causes oxidative stress, ER stress and death similar to those induced by proteasome inhibitors. Reciprocally,

role in BTZ resistance. Accordingly, ectopic expression of TXNRD2 in MM cell xenografts in immunocompromised mice blunts therapeutic effects of BTZ. Our data identify TXNRD2 as a potentially

clinically relevant target, inhibition of which is critical for proteasome inhibitor-dependent cytotoxicity, oxidative stress and ER stress. Access through your institution Buy or subscribe

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references ACKNOWLEDGEMENTS We are grateful for Dr Dominic Smiraglia for critical reading of the manuscript. This work was supported by the following NCI grants: R01 CA120244 to M.A.N. and

R01 CA121044 to K.P.L., T32 CA085183 to A.U., and Jennifer Linscott Tietgen Foundation to M.A.N. AUTHOR CONTRIBUTIONS EEF, SM, AB, AB-S and AU performed experiments; JRN, KPL, MD, VGS, LPM

and MAN analyzed the results; MD, AU, LPM and MAN designed the research, EEF and MAN wrote the manuscript. AUTHOR INFORMATION Author notes * E E Fink, S Mannava and A Bagati: These authors

contributed equally to this work. AUTHORS AND AFFILIATIONS * Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA E E Fink, S Mannava, A Bagati, A

Bianchi-Smiraglia, K Moparthy, B C Lipchick, J Ross & M A Nikiforov * Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA J R Nair, A Utley & K P Lee * National

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CORRESPONDING AUTHOR Correspondence to M A Nikiforov. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no conflict of interest. ADDITIONAL INFORMATION Supplementary Information

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permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Fink, E., Mannava, S., Bagati, A. _et al._ Mitochondrial thioredoxin reductase regulates major cytotoxicity pathways of proteasome inhibitors

in multiple myeloma cells. _Leukemia_ 30, 104–111 (2016). https://doi.org/10.1038/leu.2015.190 Download citation * Received: 14 March 2015 * Revised: 08 June 2015 * Accepted: 09 July 2015 *

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