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Multiple Myeloma, Gammopathies

Mitochondrial thioredoxin reductase regulates major cytotoxicity pathways of proteasome inhibitors in multiple myeloma cells

Leukemia volume 30, pages 104–111 (2016)Cite this article

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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, restoration of near-wildtype TXNRD2 amounts in MM cells treated with proteasome inhibitors reduces oxidative stress, ER stress and cell death by ~46%, ~35% and ~50%, respectively, compared with cells with unrestored TXNRD2 levels. Moreover, cells from three MM cell lines selected for resistance to BTZ demonstrate elevated levels of TXNRD2, indirectly confirming its functional 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.

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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.

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Author notes

  1. E E Fink, S Mannava and A Bagati: These authors contributed equally to this work.

Authors and Affiliations

  1. 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

  2. Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA

    J R Nair, A Utley & K P Lee

  3. National Research Center for Hematology, Moscow, Russian Federation

    M Drokov, L P Mendeleeva & V G Savchenko

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  1. E E Fink
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Correspondence to M A Nikiforov.

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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

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  • DOI: https://doi.org/10.1038/leu.2015.190

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