PXD039027

PXD039027 is an original dataset announced via ProteomeXchange.

Title	Proteome wide analysis of NRF2 activation
Description	Multiple cancers regulate oxidative stress by activating the transcription factor NRF2 through mutation of its negative regulator KEAP1. NRF2 has been studied extensively in KEAP1-mutant cancers, however the role of this pathway in cancers with wildtype KEAP1 remains poorly understood. To answer this question, we induced NRF2 via pharmacological inactivation of KEAP1 in a panel of 50+ non-small cell lung cancer cell lines. Unexpectedly, marked decreases in viability were observed in >13% of the cell lines—an effect that was rescued by NRF2 ablation. Genome-wide and targeted CRISPR screens revealed that NRF2 induces NADH-reductive stress, through the upregulation of the NAD+-consuming enzyme ALDH3A1. Leveraging these findings, we show that cells treated with KEAP1 inhibitors or those with endogenous KEAP1 mutations are selectively vulnerable to Complex I inhibition, which impairs NADH oxidation capacity and potentiates reductive stress. Thus, we identify reductive stress as a metabolic vulnerability in NRF2-activated lung cancers.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:42:15.076.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Maolin Ge
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2022-12-21 04:42:50	ID requested
1	2024-05-24 01:00:47	announced
⏵ 2	2024-10-22 06:42:18	announced	2024-10-22: Updated project metadata.

10.1016/j.cmet.2023.01.012;

Weiss-Sadan T, Ge M, Hayashi M, Gohar M, Yao CH, de Groot A, Harry S, Carlin A, Fischer H, Shi L, Wei TY, Adelmann CH, Wolf K, Vornb, ä, umen T, D, ü, rr BR, Takahashi M, Richter M, Zhang J, Yang TY, Vijay V, Fisher DE, Hata AN, Haigis MC, Mostoslavsky R, Bardeesy N, Papagiannakopoulos T, Bar-Peled L, NRF2 activation induces NADH-reductive stress, providing a metabolic vulnerability in lung cancer. Cell Metab, 35(3):487-503.e7(2023) [pubmed]

submitter keyword: non-small cell lung cancer,NRF2-KEAP1 pathway, Reductive stress

Liron Bar-Peled
contact affiliation	MGH Cancer Center
contact email	LBAR-PELED@mgh.harvard.edu
lab head
Maolin Ge
contact affiliation	MGH Cancer Center
contact email	mge1@mgh.harvard.edu
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/2024/05/PXD039027

PRIDE project URI

• PRIDE
  1. PXD039027
     1. Label: PRIDE project
     2. Name: Proteome wide analysis of NRF2 activation