Brusatol sensitizes endometrial hyperplasia and cancer to progestin by suppressing NRF2-TET1-AKR1C1-mediated progestin metabolism.
Journal
Laboratory investigation; a journal of technical methods and pathology
ISSN: 1530-0307
Titre abrégé: Lab Invest
Pays: United States
ID NLM: 0376617
Informations de publication
Date de publication:
12 2022
12 2022
Historique:
received:
18
01
2022
accepted:
31
05
2022
revised:
28
05
2022
pubmed:
30
8
2022
medline:
2
12
2022
entrez:
29
8
2022
Statut:
ppublish
Résumé
Progestin resistance is the main obstacle for the conservative therapy to maintain fertility in women with endometrial cancer. Brusatol was identified as an inhibitor of the NRF2 pathway; however, its impact on progestin resistance and the underlying mechanism remains unclear. Here, we found that brusatol sensitized endometrial cancer to progestin by suppressing NRF2-TET1-AKR1C1-mediated progestin metabolism. Brusatol transcriptionally suppressed AKR1C1 via modifying the hydroxymethylation status in its promoter region through TET1 inhibition. Suppression of AKR1C1 by brusatol resulted in decreased progesterone catabolism and maintained potent progesterone to inhibit endometrial cancer growth. This inhibition pattern has also been found in the established xenograft mouse and organoid models. Aberrant overexpression of AKR1C1 was found in paired endometrial hyperplasia and cancer samples from the same individuals with progestin resistance, whereas attenuated or loss of AKR1C1 was observed in post-treatment samples with well progestin response as compared with paired pre-treatment tissues. Our findings suggest that AKR1C1 expression pattern may serve as an important biomarker of progestin resistance in endometrial cancer.
Identifiants
pubmed: 36038734
doi: 10.1038/s41374-022-00816-5
pii: S0023-6837(22)03981-2
doi:
Substances chimiques
Progestins
0
brusatol
14907-98-3
NF-E2-Related Factor 2
0
Progesterone
4G7DS2Q64Y
TET1 protein, human
EC 1.-
Mixed Function Oxygenases
EC 1.-
Proto-Oncogene Proteins
0
TET1 protein, mouse
0
DNA-Binding Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1335-1345Informations de copyright
© 2022. The Author(s), under exclusive licence to United States and Canadian Academy of Pathology.
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