PXD027228

PXD027228 is an original dataset announced via ProteomeXchange.

Title	A novel small molecule that induces cytotoxicity in lung cancer cells inhibits disulfide reductases GSR and TXNRD1
Description	High-throughput phenotype-based screening of large libraries of novel compounds without known targets can identify small molecules that elicit a desired cellular response, but additional approaches are required to find and characterize their targets and mechanisms of action. Here we show that a compound termed lung cancer screen 3 (LCS3), previously selected for its ability to impair the growth of human lung adenocarcinoma (LUAD) cell lines, but not normal lung cells, induces oxidative stress and activates the NRF2 signaling pathway by generating reactive oxygen species (ROS) in sensitive LUAD cell lines. To identify the target that mediates this effect, we applied thermal proteome profiling (TPP) and uncovered the disulfide reductases GSR and TXNRD1 as LCS3 targets. Through enzymatic assays using purified protein, we confirmed that LCS3 inhibits disulfide reductase activity through a reversible, uncompetitive mechanism. Further, we demonstrate that LCS3-sensitive LUAD cells are correspondingly sensitive to the synergistic inhibition of glutathione and thioredoxin pathways. Lastly, a genome-wide CRISPR knockout screen identified the loss of NQO1 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 utility of inhibiting disulfide reductases as a therapeutic strategy for LUAD.
HostingRepository	PRIDE
AnnounceDate	2022-02-23
AnnouncementXML	Submission_2022-02-23_09:16:54.337.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Xu Zhang
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2021-07-12 01:42:02	ID requested
⏵ 1	2022-02-23 09:16:55	announced

Johnson FD, Ferrarone J, Liu A, Brandst, ä, dter C, Munuganti R, Farnsworth DA, Lu D, Luu J, Sihota T, Jansen S, Nagelberg A, Shi R, Forcina GC, Zhang X, Cheng GSW, Spencer Miko SE, de Rappard-Yuswack G, Sorensen PH, Dixon SJ, Guha U, Becker K, Djaballah H, Somwar R, Varmus H, Morin GB, Lockwood WW, Characterization of a small molecule inhibitor of disulfide reductases that induces oxidative stress and lethality in lung cancer cells. Cell Rep, 38(6):110343(2022) [pubmed]

submitter keyword: lung cancer, thermal proteome profiling, LCS3-sensitive LUAD cells

Willian Lockwood
contact affiliation	Department of Medical Genetics, University of British Columbia, Vancouver, Canada
contact email	wlockwood@bccrc.ca
lab head
Xu Zhang
contact affiliation	NIH/NCI
contact email	xu.zhang@nih.gov
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD027228
     1. Label: PRIDE project
     2. Name: A novel small molecule that induces cytotoxicity in lung cancer cells inhibits disulfide reductases GSR and TXNRD1