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A CRISPR screen identifies redox vulnerabilities for KEAP1/NRF2 mutant non-small cell lung cancer.
- Source :
-
Redox biology [Redox Biol] 2022 Aug; Vol. 54, pp. 102358. Date of Electronic Publication: 2022 Jun 02. - Publication Year :
- 2022
-
Abstract
- The redox regulator NRF2 is hyperactivated in a large percentage of non-small cell lung cancer (NSCLC) cases, which is associated with chemotherapy and radiation resistance. To identify redox vulnerabilities for KEAP1/NRF2 mutant NSCLC, we conducted a CRISPR-Cas9-based negative selection screen for antioxidant enzyme genes whose loss sensitized cells to sub-lethal concentrations of the superoxide (O <subscript>2</subscript> <superscript>•</superscript> <superscript>-</superscript> ) -generating drug β-Lapachone. While our screen identified expected hits in the pentose phosphate pathway, the thioredoxin-dependent antioxidant system, and glutathione reductase, we also identified the mitochondrial superoxide dismutase 2 (SOD2) as one of the top hits. Surprisingly, β-Lapachone did not generate mitochondrial O <subscript>2</subscript> <superscript>•</superscript> <superscript>-</superscript> but rather SOD2 loss enhanced the efficacy of β-Lapachone due to loss of iron-sulfur protein function, loss of mitochondrial ATP maintenance and deficient NADPH production. Importantly, inhibition of mitochondrial electron transport activity sensitized cells to β-Lapachone, demonstrating that these effects may be translated to increase ROS sensitivity therapeutically.<br /> (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Antioxidants metabolism
Humans
Kelch-Like ECH-Associated Protein 1 genetics
Kelch-Like ECH-Associated Protein 1 metabolism
NF-E2-Related Factor 2 genetics
NF-E2-Related Factor 2 metabolism
Oxidation-Reduction
Carcinoma, Non-Small-Cell Lung genetics
Carcinoma, Non-Small-Cell Lung metabolism
Lung Neoplasms genetics
Lung Neoplasms metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2213-2317
- Volume :
- 54
- Database :
- MEDLINE
- Journal :
- Redox biology
- Publication Type :
- Academic Journal
- Accession number :
- 35667246
- Full Text :
- https://doi.org/10.1016/j.redox.2022.102358