Characterization of a small molecule inhibitor of disulfide reductases that induces oxidative stress and lethality in lung cancer cells Journal Article

   


Authors: Johnson, F. D.; Ferrarone, J.; Liu, A.; Brandstädter, C.; Munuganti, R.; Farnsworth, D. A.; Lu, D.; Luu, J.; Sihota, T.; Jansen, S.; Nagelberg, A.; Shi, R.; Forcina, G. C.; Zhang, X.; Cheng, G. S. W.; Spencer Miko, S. E.; de Rappard-Yuswack, G.; Sorensen, P. H.; Dixon, S. J.; Guha, U.; Becker, K.; Djaballah, H.; Somwar, R.; Varmus, H.; Morin, G. B.; Lockwood, W. W.
Article Title: Characterization of a small molecule inhibitor of disulfide reductases that induces oxidative stress and lethality in lung cancer cells
Abstract: Phenotype-based screening can identify small molecules that elicit a desired cellular response, but additional approaches are required to characterize their targets and mechanisms of action. Here, we show that a compound termed LCS3, which selectively impairs the growth of human lung adenocarcinoma (LUAD) cells, induces oxidative stress. To identify the target that mediates this effect, we use thermal proteome profiling (TPP) and uncover the disulfide reductases GSR and TXNRD1 as targets. We confirm through enzymatic assays that LCS3 inhibits disulfide reductase activity through a reversible, uncompetitive mechanism. Further, we demonstrate that LCS3-sensitive LUAD cells are sensitive to the synergistic inhibition of glutathione and thioredoxin pathways. Lastly, a genome-wide CRISPR knockout screen identifies NQO1 loss as a mechanism of LCS3 resistance. This work highlights the ability of TPP to uncover targets of small molecules identified by high-throughput screens and demonstrates the potential therapeutic utility of inhibiting disulfide reductases in LUAD. © 2022
Keywords: lung cancer; reactive oxygen species; glutathione; thioredoxin; redox homeostasis; small molecule screen; thermal proteome profiling
Journal Title: Cell Reports
Volume: 38
Issue: 6
ISSN: 2211-1247
Publisher: Cell Press  
Date Published: 2022-02-08
Start Page: 110343
Language: English
DOI: 10.1016/j.celrep.2022.110343
PUBMED: 35139387
PROVIDER: scopus
PMCID: PMC8904132
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85124220911&doi=10.1016%2fj.celrep.2022.110343&partnerID=40&md5=2d8d35ef54509185cb15aacb0ab32cfa
Notes: Article -- Export Date: 1 March 2022 -- Source: Scopus
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MSK Authors
  1. Romel Somwar
    110 Somwar
  2. Hakim Djaballah
    101 Djaballah
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