Thioredoxin reductase is a major regulator of metabolism in leukemia cells

被引：19

作者：

Karunanithi, Sheelarani ^{[1
,2
]}

Liu, Ruifu ^{[1
]}

Hou, Yongchun ^{[2
]}

Gonzalez, Giancarlo ^{[1
]}

Oldford, Natasha ^{[1
]}

Roe, Anne Jessica ^{[1
,2
]}

Idipilly, Nethrie ^{[1
,2
]}

Gupta, Kalpana ^{[1
]}

Amara, Chandra Sekhar ^{[3
]}

Putluri, Satwikreddy ^{[3
]}

Lee, Grace Kyueun ^{[1
]}

Valentin-Goyco, Juan ^{[1
]}

Stetson, Lindsay ^{[1
]}

Moreton, Stephen A. ^{[2
]}

Putluri, Vasanta ^{[4
]}

Kavuri, Shyam M. ^{[5
,6
]}

Saunthararajah, Yogen ^{[7
]}

de Lima, Marcos ^{[8
]}

Tochtrop, Gregory P. ^{[9
]}

Putluri, Nagireddy ^{[3
,4
]}

Wald, David N. ^{[1
,2
,10
]}

机构：

[1] Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA

[2] CuronBiotech Inc, Cleveland, OH 44106 USA

[3] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA

[4] Baylor Coll Med, Alkek Ctr Mol Discovery, Dan L Duncan Canc Ctr, Adv Technol Core, Houston, TX 77030 USA

[5] Baylor Coll Med, Lester & Sue Smith Breast Ctr, Houston, TX 77030 USA

[6] Baylor Coll Med, Dept Med, Houston, TX 77030 USA

[7] Cleveland Clin Fdn, Dept Translat Hematol & Oncol Res, 9500 Euclid Ave, Cleveland, OH 44195 USA

[8] Univ Hosp Cleveland, Dept Med, Med Ctr, 2074 Abington Rd, Cleveland, OH 44106 USA

[9] Case Western Reserve Univ, Dept Chem, Cleveland, OH 44106 USA

[10] Louis Stokes Cleveland VA Med Ctr, Dept Pathol, Cleveland, OH 44106 USA

来源：

ONCOGENE | 2021年 / 40卷 / 33期

关键词：

OXIDATIVE STRESS; INHIBITION; APOPTOSIS; SYSTEM;

D O I：

10.1038/s41388-021-01924-0

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：5236 / 5246

页数：11

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