Distinct Nrf2 Signaling Thresholds Mediate Lung Tumor Initiation and Progression.
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
15 06 2023
15 06 2023
Historique:
received:
08
12
2022
revised:
03
03
2023
accepted:
12
04
2023
medline:
16
6
2023
pubmed:
17
4
2023
entrez:
16
4
2023
Statut:
ppublish
Résumé
Mutations in the KEAP1-NRF2 (Kelch-like ECH-associated protein 1-nuclear factor-erythroid 2 p45-related factor 2) pathway occur in up to a third of non-small cell lung cancer (NSCLC) cases and often confer resistance to therapy and poor outcomes. Here, we developed murine alleles of the KEAP1 and NRF2 mutations found in human NSCLC and comprehensively interrogated their impact on tumor initiation and progression. Chronic NRF2 stabilization by Keap1 or Nrf2 mutation was not sufficient to induce tumorigenesis, even in the absence of tumor suppressors, p53 or LKB1. When combined with KrasG12D/+, constitutive NRF2 activation promoted lung tumor initiation and early progression of hyperplasia to low-grade tumors but impaired their progression to advanced-grade tumors, which was reversed by NRF2 deletion. Finally, NRF2 overexpression in KEAP1 mutant human NSCLC cell lines was detrimental to cell proliferation, viability, and anchorage-independent colony formation. Collectively, these results establish the context-dependence and activity threshold for NRF2 during the lung tumorigenic process. Stabilization of the transcription factor NRF2 promotes oncogene-driven tumor initiation but blocks tumor progression, indicating distinct, threshold-dependent effects of the KEAP1/NRF2 pathway in different stages of lung tumorigenesis.
Identifiants
pubmed: 37062029
pii: 725886
doi: 10.1158/0008-5472.CAN-22-3848
pmc: PMC10267679
doi:
Substances chimiques
Kelch-Like ECH-Associated Protein 1
0
NF-E2-Related Factor 2
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1953-1967Subventions
Organisme : NCI NIH HHS
ID : P30 CA076292
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA230042
Pays : United States
Informations de copyright
©2023 The Authors; Published by the American Association for Cancer Research.
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