Pituitary adenomas evade apoptosis via noxa deregulation in Cushing's disease.
CP: Cancer
CP: Molecular biology
Cushing’s disease
DNA methylation
bortezomib
preclinical testing
proteasome
single-cell RNA-seq
sporadic pituitary adenoma
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
23 08 2022
23 08 2022
Historique:
received:
14
06
2021
revised:
03
06
2022
accepted:
26
07
2022
entrez:
24
8
2022
pubmed:
25
8
2022
medline:
27
8
2022
Statut:
ppublish
Résumé
Sporadic pituitary adenomas occur in over 10% of the population. Hormone-secreting adenomas, including those causing Cushing's disease (CD), cause severe morbidity and early mortality. Mechanistic studies of CD are hindered by a lack of in vitro models and control normal human pituitary glands. Here, we surgically annotate adenomas and adjacent normal glands in 25 of 34 patients. Using single-cell RNA sequencing (RNA-seq) analysis of 27594 cells, we identify CD adenoma transcriptomic signatures compared with adjacent normal cells, with validation by bulk RNA-seq, DNA methylation, qRT-PCR, and immunohistochemistry. CD adenoma cells include a subpopulation of proliferating, terminally differentiated corticotrophs. In CD adenomas, we find recurrent promoter hypomethylation and transcriptional upregulation of PMAIP1 (encoding pro-apoptotic BH3-only bcl-2 protein noxa) but paradoxical noxa downregulation. Using primary CD adenoma cell cultures and a corticotroph-enriched mouse cell line, we find that selective proteasomal inhibition with bortezomib stabilizes noxa and induces apoptosis, indicating its utility as an anti-tumor agent.
Identifiants
pubmed: 36001971
pii: S2211-1247(22)01040-3
doi: 10.1016/j.celrep.2022.111223
pmc: PMC9527711
mid: NIHMS1833590
pii:
doi:
Substances chimiques
Adrenocorticotropic Hormone
9002-60-2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
111223Subventions
Organisme : Intramural NIH HHS
ID : ZIA NS003150
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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