ATM inhibition enhances Auranofin-induced oxidative stress and cell death in lung cell lines.
A549 Cells
Animals
Ataxia Telangiectasia Mutated Proteins
/ antagonists & inhibitors
Auranofin
/ pharmacology
Cell Death
/ drug effects
HEK293 Cells
Humans
Mice
Morpholines
/ pharmacology
Oxidative Stress
/ drug effects
Protein Kinase Inhibitors
/ pharmacology
Pyrones
/ pharmacology
Thioredoxin-Disulfide Reductase
/ antagonists & inhibitors
Thioredoxins
/ genetics
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2020
2020
Historique:
received:
27
08
2020
accepted:
02
12
2020
entrez:
18
12
2020
pubmed:
19
12
2020
medline:
18
2
2021
Statut:
epublish
Résumé
Ataxia-Telangiectasia (A-T), a pleiotropic chromosomal breakage syndrome, is caused by the loss of the kinase Ataxia-telangiectasia mutated (ATM). ATM is not only involved in the response to DNA damage, but also in sensing and counteracting oxidative stress. Since a disturbed redox balance has been implicated in the pathophysiology of A-T lung disease, we aimed to further explore the interplay between ATM and oxidative stress in lung cells. Using a kinetic trapping approach, we could demonstrate an interaction between the trapping mutant TRX1-CS and ATM upon oxidative stress. We could further show that combined inhibition of thioredoxin reductase (TrxR) and ATM kinase activity, using Auranofin and KU55933 respectively, induced an increase in cellular reactive oxygen species (ROS) levels and protein oxidation in lung cells. Furthermore, ATM inhibition sensitized lung cells to Auranofin-induced cell death that could be rescued by ROS scavengers. As a consequence, targeted reduction of ATM by TRX1 could serve as a regulator of oxidative ATM activation and contribute to the maintenance of the cellular redox homeostasis. These results highlight the importance of the redox-active function of ATM in preventing ROS accumulation and cell death in lung cells.
Identifiants
pubmed: 33338048
doi: 10.1371/journal.pone.0244060
pii: PONE-D-20-26902
pmc: PMC7748142
doi:
Substances chimiques
2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one
0
Morpholines
0
Protein Kinase Inhibitors
0
Pyrones
0
Auranofin
3H04W2810V
Thioredoxins
52500-60-4
Thioredoxin-Disulfide Reductase
EC 1.8.1.9
ATM protein, human
EC 2.7.11.1
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0244060Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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