Thioredoxin Reductase Is a Major Regulator of Metabolism in Leukemia Cells

Authors

Sheelarani Karunanithi
Ruifu Liu
Yongchun Hou
Giancarlo Gonzalez
Natasha Oldford
Anne Jessica Roe
Nethrie Idipilly
Kalpana Gupta
Chandra Sekhar Amara
Satwikreddy Putluri
Grace Kyueun Lee
Juan Valentin-Goyco
Lindsay Stetson
Stephen A Moreton
Vasanta Putluri
Shyam M Kavuri
Yogen Saunthararajah
Marcos de Lima
Gregory P Tochtrop
Nagireddy Putluri
David N Wald

Publication Date

8-1-2021

Journal

Oncogene

DOI

10.1038/s41388-021-01924-0

PMID

34239044

PMCID

PMC8380733

PubMedCentral® Posted Date

1-8-2022

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Animals, Humans, Mice, Cell Line, Tumor, Cell Proliferation, Glycolysis, Leukemia, Myeloid, Acute, Pentose Phosphate Pathway, Thioredoxin-Disulfide Reductase, securinine, thioredoxin reductase, AML, cancer cell metabolism, mitochondrial metabolism

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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