PXD030294

PXD030294 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	Phenotype-based screening can identify unique 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 used thermal proteome profiling (TPP) and uncovered the disulfide reductases GSR and TXNRD1 as targets. We confirmed 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 identified 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.
HostingRepository	PRIDE
AnnounceDate	2022-05-25
AnnouncementXML	Submission_2022-05-25_09:30:41.363.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Fraser Johnson
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2021-12-10 02:31:03	ID requested
⏵ 1	2022-05-25 09:30:42	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: Thermal proteome profiling, LCS3

William Lockwood
contact affiliation	University of British Columbia
contact email	wlockwood@bccrc.ca
lab head
Fraser Johnson
contact affiliation	University of British Columbia
contact email	f.johnson@alumni.ubc.ca
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2022/04/PXD030294

PRIDE project URI

• PRIDE
  1. PXD030294
     1. Label: PRIDE project
     2. Name: A novel small molecule that induces cytotoxicity in lung cancer cells inhibits disulfide reductases GSR and TXNRD1