Celecoxib reduces glucocorticoids in vitro and in a mouse model with adrenocortical hyperplasia.

Abstract

Primary pigmented nodular adrenocortical disease (PPNAD), whether in the context of Carney complex (CNC) or isolated, leads to ACTH-independent Cushing's syndrome (CS). CNC and PPNAD are caused typically by inactivating mutations of PRKAR1A, a gene coding for the type 1a regulatory subunit (R1α) of cAMP-dependent protein kinase (PKA). Mice lacking Prkar1a, specifically in the adrenal cortex (AdKO) developed CS caused by bilateral adrenal hyperplasia (BAH), which is formed from the abnormal proliferation of fetal-like adrenocortical cells. Celecoxib is a cyclooxygenase 2 (COX2) inhibitor. In bone, Prkar1a inhibition is associated with COX2 activation and prostaglandin E2 (PGE2) production that, in turn, activates proliferation of bone stromal cells. We hypothesized that COX2 inhibition may have an effect in PPNAD. In vitro treatment of human cell lines, including one from a patient with PPNAD, with celecoxib resulted in decreased cell viability. We then treated AdKO and control mice with 1500 mg/kg celecoxib or vehicle. Celecoxib treatment led to decreased PGE2 and corticosterone levels, reduced proliferation and increased apoptosis of adrenocortical cells, and decreased steroidogenic gene expression. We conclude that, in vitro and in vivo, celecoxib led to decreased steroidogenesis. In a mouse model of PPNAD, celecoxib caused histological changes that, at least in part, reversed BAH and this was associated with a reduction of corticosterone levels.

• Authors: Sisi Liu, Emmanouil Saloustros, Annabel Berthon, Matthew F Starost, Isabelle Sahut-Barnola, Paraskevi Salpea, Eva Szarek, Fabio R Faucz, Antoine Martinez, Constantine A Stratakis
• Journal: Endocrine-related cancer (Endocr Relat Cancer) Vol. 23 Issue 1 Pg. 15-25 (Jan 2016) ISSN: 1479-6821 [Electronic] England
• PMID: 26438728 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
• Copyright: © 2016 Society for Endocrinology.

Chemical References

• Glucocorticoids
• Celecoxib

Topics

• Adrenal Cortex (drug effects, metabolism, pathology)
• Animals
• Celecoxib (pharmacology)
• Cushing Syndrome (etiology, metabolism, pathology)
• Disease Models, Animal
• Down-Regulation (drug effects)
• Female
• Glucocorticoids (metabolism)
• HEK293 Cells
• Humans
• Hyperplasia (complications, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Tumor Cells, Cultured