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Pituitary adenomas evade apoptosis via noxa deregulation in Cushing’s disease
- Source :
- Cell Reports; August 2022, Vol. 40 Issue: 8
- Publication Year :
- 2022
-
Abstract
- 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 vitromodels 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.
Details
- Language :
- English
- ISSN :
- 22111247
- Volume :
- 40
- Issue :
- 8
- Database :
- Supplemental Index
- Journal :
- Cell Reports
- Publication Type :
- Periodical
- Accession number :
- ejs61905689
- Full Text :
- https://doi.org/10.1016/j.celrep.2022.111223