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Thioredoxin reductase is a major regulator of metabolism in leukemia cells

Oncogene volume 40, pages 5236–5246 (2021)Cite this article

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Abstract

Despite the fact that AML is the most common acute leukemia in adults, patient outcomes are poor necessitating the development of novel therapies. We identified that inhibition of Thioredoxin Reductase (TrxR) is a promising strategy for AML and report a highly potent and specific inhibitor of TrxR, S-250. Both pharmacologic and genetic inhibition of TrxR impairs the growth of human AML in mouse models. We found that TrxR inhibition leads to a rapid and marked impairment of metabolism in leukemic cells subsequently leading to cell death. TrxR was found to be a major and direct regulator of metabolism in AML cells through impacts on both glycolysis and the TCA cycle. Studies revealed that TrxR directly regulates GAPDH leading to a disruption of glycolysis and an increase in flux through the pentose phosphate pathway (PPP). The combined inhibition of TrxR and the PPP led to enhanced leukemia growth inhibition. Overall, TrxR abrogation, particularly with S-250, was identified as a promising strategy to disrupt AML metabolism.

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Fig. 1: S-250 potently decreases the viability of AML cell lines and patient samples.
Fig. 2: S-250 irreversibly targets Thioredoxin reductase.
Fig. 3: S-250 decreases leukemic burden in circulating AML mice models.
Fig. 4: TrxR1 levels determine sensitivity to S-250.
Fig. 5: S-250 treatment induces metabolic changes in AML cells.
Fig. 6: S-250 treatment impairs mitochondrial metabolism.

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Acknowledgements

We thank the Proteomics facility at the Cleveland Clinic Lerner Research Institute for analysis of the mass spectrometry data. This research was supported by the Hematopoietic Biorepository and Cellular Therapy, Athymic Animal and Preclinical Therapeutics, Proteomics and Cytometry and Imaging Microscopy Shared Resources of the Case Comprehensive Cancer Center (P30CA043703). The research was also supported by the NIH grant R43CA22870 (D.N.W. and Y.H.) and VA medical center grant I01BX004995. Targeted metabolomics performed at the University of Michigan metabolomics core was supported by the NIH grant U24DK097153. This research was supported by American Cancer Society (ACS) Award 127430-RSG-15-105-01-CNE (N.P.), NIH/NCI R01CA220297 (N.P), and NIH/NCI R01CA216426 (N.P.). W81XWH-18-1-0035 and W81XWH-18-1-0084 to S.M.K.

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Authors and Affiliations

  1. Department of Pathology, Case Western Reserve University, Cleveland, OH, USA

    Sheelarani Karunanithi, Ruifu Liu, Giancarlo Gonzalez, Natasha Oldford, Anne Jessica Roe, Nethrie Idipilly, Kalpana Gupta, Grace Kyueun Lee, Juan Valentin-Goyco, Lindsay Stetson & David N. Wald

  2. CuronBiotech Inc, Cleveland, OH, USA

    Sheelarani Karunanithi, Yongchun Hou, Anne Jessica Roe, Nethrie Idipilly, Stephen A. Moreton & David N. Wald

  3. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    Chandra Sekhar Amara, Satwikreddy Putluri & Nagireddy Putluri

  4. Dan L. Duncan Cancer Center, Advanced Technology Core, Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, TX, USA

    Vasanta Putluri & Nagireddy Putluri

  5. Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA

    Shyam M. Kavuri

  6. Department of Medicine, Baylor College of Medicine, Houston, TX, USA

    Shyam M. Kavuri

  7. Department of Translational Hematology and Oncology Research, Cleveland Clinic Foundation, Cleveland, OH, USA

    Yogen Saunthararajah

  8. Department of Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH, USA

    Marcos de Lima

  9. Department of Chemistry, Case Western Reserve University, Cleveland, OH, USA

    Gregory P. Tochtrop

  10. Department of Pathology, Louis Stokes Cleveland VA Medical Center, Cleveland, OH, USA

    David N. Wald

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Contributions

SK and DNW designed the studies, wrote the manuscript and analyzed the data. DNW supervised the study. SK, RL, GL, YH, NO, SAM, JVG, AR, KG, and NI performed experiments. LS analyzed DARTS data. YS and ML provided reagents and assistance with data analysis. VP, CSA, SP, SMK, NP performed metabolomics data peak integration of peak and data analysis. GPT guided the chemistry studies. VP, CSA, and NP were involved in method development for metabolites. SMK guided SP on data analysis. NP and SMK, SK and DNW edited the manuscript.

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Correspondence to David N. Wald.

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Competing interests

DNW is an inventor on patents related to S-250 and his employer Case Western Reserve University is the owner of patents related to S-250. SMK is a stakeholder in NeoZenome Therapeutics Inc. No other authors have any conflicts of interest with this study.

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Karunanithi, S., Liu, R., Hou, Y. et al. Thioredoxin reductase is a major regulator of metabolism in leukemia cells. Oncogene 40, 5236–5246 (2021). https://doi.org/10.1038/s41388-021-01924-0

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