title: 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.forename: Sisi
authors.initials: S
authors.lastname: Liu
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Saloustros
authors.forename: Annabel
authors.initials: A
authors.lastname: Berthon
authors.affiliation: Section on Endocrinology and Genetics (SEGEN)Program on Developmental Endocrinology and Genetics (PDEGEN), <ce:italic>Eunice Kennedy Shriver</ce:italic> National Institute of Child Health and Human Development (NICHD), National Institutes of Health, 10 Center Drive, Building 10-Clinical Research Center, Room 1-3330, Bethesda, Maryland 20892, USAOffice of Research Services (ORS)Division of Veterinary Resources (DVR), Office of the Director (OD), National Institutes of Health, Bethesda, Maryland 20892, USACNRS UMR6247Génétique Reproduction et Développement, Clermont Université, Aubière, France.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Starost
authors.affiliation: Section on Endocrinology and Genetics (SEGEN)Program on Developmental Endocrinology and Genetics (PDEGEN), <ce:italic>Eunice Kennedy Shriver</ce:italic> National Institute of Child Health and Human Development (NICHD), National Institutes of Health, 10 Center Drive, Building 10-Clinical Research Center, Room 1-3330, Bethesda, Maryland 20892, USAOffice of Research Services (ORS)Division of Veterinary Resources (DVR), Office of the Director (OD), National Institutes of Health, Bethesda, Maryland 20892, USACNRS UMR6247Génétique Reproduction et Développement, Clermont Université, Aubière, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Sahut-Barnola
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Salpea
authors.forename: Eva
authors.initials: E
authors.lastname: Szarek
authors.forename: Fabio R
authors.initials: FR
authors.lastname: Faucz
authors.affiliation: Section on Endocrinology and Genetics (SEGEN)Program on Developmental Endocrinology and Genetics (PDEGEN), <ce:italic>Eunice Kennedy Shriver</ce:italic> National Institute of Child Health and Human Development (NICHD), National Institutes of Health, 10 Center Drive, Building 10-Clinical Research Center, Room 1-3330, Bethesda, Maryland 20892, USAOffice of Research Services (ORS)Division of Veterinary Resources (DVR), Office of the Director (OD), National Institutes of Health, Bethesda, Maryland 20892, USACNRS UMR6247Génétique Reproduction et Développement, Clermont Université, Aubière, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Martinez
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
mesh_terms: D000302:Adrenal Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D000068579:Celecoxib / Q000494:pharmacology*; D003480:Cushing Syndrome / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D006965:Hyperplasia / Q000150:complications / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014407:Tumor Cells, Cultured
chemical_list: D005938:Glucocorticoids; D000068579:Celecoxib
keywords: adrenal tumors; cAMP; celecoxib; primary pigmented nodular adrenocortical disease (PPNAD); prostaglandin E2