PPARG dysregulation as a potential molecular target in adrenal Cushing's syndrome

• Published in: Frontiers in endocrinology (Lausanne) Vol. 14; p. 1265794
• Main Authors: Vetrivel, Sharmilee, Tamburello, Mariangela, Oßwald, Andrea, Zhang, Ru, Khan, Ali, Jung, Sara, Baker, Jessica E, Rainey, William E, Nowak, Elisabeth, Altieri, Barbara, Detomas, Mario, Watts, Deepika, Williams, Tracy Ann, Wielockx, Ben, Beuschlein, Felix, Reincke, Martin, Sbiera, Silviu, Riester, Anna
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 30-11-2023
• Subjects: Adrenalectomy - methods; adrenocortical cell line; cortisol; Cushing Syndrome - drug therapy; Cushing Syndrome - genetics; Cushing Syndrome - surgery; Endocrinology; Humans; Hydrocortisone - metabolism; hypercortisolism; Hyperplasia; PPAR gamma - genetics; rosiglitazone; steroidome; transcriptome; hypercortisolism; cortisol; primary bilateral macronodular hype; steroidome; transcriptome; rosiglitazone; adrenocortical cell line
• ISSN: 1664-2392; 1664-2392
• DOI: 10.3389/fendo.2023.1265794

We performed a transcriptomic analysis of adrenal signaling pathways in various forms of endogenous Cushing's syndrome (CS) to define areas of dysregulated and druggable targets.
Next-generation sequencing was performed on adrenal samples of patients with primary bilateral macronodular adrenal hyperplasia (PBMAH, n=10) and control adrenal samples (n=8). The validation groups included cortisol-producing adenoma (CPA, n=9) and samples from patients undergoing bilateral adrenalectomy for Cushing's disease (BADX-CD, n=8).
findings were further characterized using three adrenocortical cell-lines (NCI-H295R, CU-ACC2, MUC1).
Pathway mapping based on significant expression patterns identified PPARG (peroxisome proliferator-activated receptor gamma) pathway as the top hit. Quantitative PCR (QPCR) confirmed that
(l2fc<-1.5) and related genes -
(l2fc<-5.5),
(l2fc<-4.1) and
(l2fc<-3.3) - were significantly downregulated (p<0.005) in PBMAH. Significant downregulation of
was also found in BADX-CD (l2fc<-1.9, p<0.0001) and CPA (l2fc<-1.4, p<0.0001).
studies demonstrated that the PPARG activator rosiglitazone resulted in decreased cell viability in MUC1 and NCI-H295R (p<0.0001). There was also a significant reduction in the production of aldosterone, cortisol, and cortisone in NCI-H295R and in Dihydrotestosterone (DHT) in MUC1 (p<0.05), respectively.
This therapeutic effect was independent of the actions of ACTH, postulating a promising application of
activation in endogenous hypercortisolism.