Proteome wide analysis of NRF2 activation

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hepatocyte, Cell Culture

DISEASE(S): Non-small Cell Lung Carcinoma

SUBMITTER: Maolin Ge  

LAB HEAD: Liron Bar-Peled

PROVIDER: PXD039027 | Pride | 2024-05-24

REPOSITORIES: Pride