학술논문
Thioredoxin reductase is a major regulator of metabolism in leukemia cells
Document Type
Report
Author
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
Source
Oncogene. August 19, 2021, Vol. 40 Issue 33, p5236, 11 p.
Subject
Language
English
ISSN
0950-9232
Abstract
Author(s): Sheelarani Karunanithi [sup.1] [sup.2] , Ruifu Liu [sup.1] , Yongchun Hou [sup.2] , Giancarlo Gonzalez [sup.1] , Natasha Oldford [sup.1] , Anne Jessica Roe [sup.1] [sup.2] , Nethrie Idipilly [...]
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.
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.