Thioredoxin reductase is a major regulator of metabolism in leukemia cells

• Published in: Oncogene Vol. 40; no. 33; pp. 5236 - 5246
• Main Authors: Karunanithi, Sheelarani, Liu, Ruifu, Hou, Yongchun, Gonzalez, Giancarlo, Oldford, Natasha, Roe, Anne Jessica, Idipilly, Nethrie, Gupta, Kalpana, Amara, Chandra Sekhar, Putluri, Satwikreddy, Lee, Grace Kyueun, Valentin-Goyco, Juan, Stetson, Lindsay, Moreton, Stephen A, Putluri, Vasanta, Kavuri, Shyam M, Saunthararajah, Yogen, de Lima, Marcos, Tochtrop, Gregory P, Putluri, Nagireddy, Wald, David N
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 19.08.2021
• Subjects: Acute myeloid leukemia; Animal models; Cell Death; Cell metabolism; Cellular control mechanisms; Citric Acid Cycle; Genetic aspects; Glyceraldehyde-3-phosphate dehydrogenase; Glycolysis; Health aspects; Humans; Leukemia; Metabolism; Oxidoreductases; Pentose Phosphate Pathway; Thioredoxin; Thioredoxin-Disulfide Reductase; Tricarboxylic acid cycle; United States
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/s41388-021-01924-0

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.