The NRF2-p97-NRF2 negative feedback loop.
Arsenic
Cancer
Nrf2
Oxidative stress
Proteostasis
p97
Journal
Redox biology
ISSN: 2213-2317
Titre abrégé: Redox Biol
Pays: Netherlands
ID NLM: 101605639
Informations de publication
Date de publication:
09 2023
09 2023
Historique:
received:
19
05
2023
revised:
15
07
2023
accepted:
04
08
2023
medline:
21
8
2023
pubmed:
14
8
2023
entrez:
13
8
2023
Statut:
ppublish
Résumé
p97 is a ubiquitin-targeted ATP-dependent segregase that regulates proteostasis, in addition to a variety of other cellular functions. Previously, we demonstrated that p97 negatively regulates NRF2 by extracting ubiquitylated NRF2 from the KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex, facilitating proteasomal destruction. In the current study, we identified p97 as an NRF2-target gene that contains a functional ARE, indicating the presence of an NRF2-p97-NRF2 negative feedback loop that maintains redox homeostasis. Using CRISPR/Cas9 genome editing, we generated endogenous p97 ARE-mutated BEAS-2B cell lines. These p97 ARE-mutated cell lines exhibit altered expression of p97 and NRF2, as well as a compromised response to NRF2 inducers. Importantly, we also found a positive correlation between NRF2 activation and p97 expression in human cancer patients. Finally, using chronic arsenic-transformed cell lines, we demonstrated a synergistic effect of NRF2 and p97 inhibition in killing cancer cells with high NRF2 and p97 expression. Our study suggests dual upregulation of NRF2 and p97 occurs in certain types of cancers, suggesting that inhibition of both NRF2 and p97 could be a promising treatment strategy for stratified cancer patients.
Identifiants
pubmed: 37573837
pii: S2213-2317(23)00240-9
doi: 10.1016/j.redox.2023.102839
pmc: PMC10428046
pii:
doi:
Substances chimiques
Carrier Proteins
0
Cullin Proteins
0
Kelch-Like ECH-Associated Protein 1
0
NF-E2-Related Factor 2
0
NFE2L2 protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
102839Subventions
Organisme : NIEHS NIH HHS
ID : R35 ES031575
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES031463
Pays : United States
Organisme : NIEHS NIH HHS
ID : P30 ES006694
Pays : United States
Informations de copyright
Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐ The authors declare the following financial interests/personal relationships which may be considered as potential competing interests.
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