Thioredoxin reductase is a major regulator of metabolism in leukemia cells.

Autor: Karunanithi S; Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.; CuronBiotech Inc, Cleveland, OH, USA., Liu R; Department of Pathology, Case Western Reserve University, Cleveland, OH, USA., Hou Y; CuronBiotech Inc, Cleveland, OH, USA., Gonzalez G; Department of Pathology, Case Western Reserve University, Cleveland, OH, USA., Oldford N; Department of Pathology, Case Western Reserve University, Cleveland, OH, USA., Roe AJ; Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.; CuronBiotech Inc, Cleveland, OH, USA., Idipilly N; Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.; CuronBiotech Inc, Cleveland, OH, USA., Gupta K; Department of Pathology, Case Western Reserve University, Cleveland, OH, USA., Amara CS; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA., Putluri S; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA., Lee GK; Department of Pathology, Case Western Reserve University, Cleveland, OH, USA., Valentin-Goyco J; Department of Pathology, Case Western Reserve University, Cleveland, OH, USA., Stetson L; Department of Pathology, Case Western Reserve University, Cleveland, OH, USA., Moreton SA; CuronBiotech Inc, Cleveland, OH, USA., Putluri V; Dan L. Duncan Cancer Center, Advanced Technology Core, Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, TX, USA., Kavuri SM; Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.; Department of Medicine, Baylor College of Medicine, Houston, TX, USA., Saunthararajah Y; Department of Translational Hematology and Oncology Research, Cleveland Clinic Foundation, Cleveland, OH, USA., de Lima M; Department of Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH, USA., Tochtrop GP; Department of Chemistry, Case Western Reserve University, Cleveland, OH, USA., Putluri N; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.; Dan L. Duncan Cancer Center, Advanced Technology Core, Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, TX, USA., Wald DN; Department of Pathology, Case Western Reserve University, Cleveland, OH, USA. dnw@case.edu.; CuronBiotech Inc, Cleveland, OH, USA. dnw@case.edu.; Department of Pathology, Louis Stokes Cleveland VA Medical Center, Cleveland, OH, USA. dnw@case.edu.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2021 Aug; Vol. 40 (33), pp. 5236-5246. Date of Electronic Publication: 2021 Jul 08.
DOI: 10.1038/s41388-021-01924-0
Abstrakt: 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.
(© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)
Databáze: MEDLINE
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