title: Activation of the dopamine receptor type-2 (DRD2) promoter by 9-cis retinoic acid in a cellular model of Cushing's disease mediates the inhibition of cell proliferation and ACTH secretion without a complete corticotroph-to-melanotroph transdifferentiation.
abstract: Cushing's disease (CD) is a rare condition in which hypercortisolemia is secondary to excessive ACTH release from a pituitary corticotroph adenoma. CD is associated with significant morbidity and mortality, and a safe therapy that effectively targets the pituitary tumor is still lacking. Retinoic acid (RA) and dopamine agonists (DAs) have recently been considered as monotherapy in CD patients, and satisfactory results have been reported, albeit in a limited number of patients. Given the permissive role of RA on the dopamine receptor type-2 (DRD2), the aim of the present study was to see whether a combination of 9-cis RA and the DA bromocriptine (Br) might represent a possible treatment for CD. Here we show that 9-cis RA induces a functional DRD2 in the pituitary corticotroph cell line AtT20, and increases cell sensitivity to Br via a mechanism only partially related to corticotroph-to-melanotroph transdifferentiation. In addition, 9-cis RA and Br act synergistically to modulate cell viability, with favorable implications for clinical use. In nearly 45% of corticotropinoma-derived primary cultures, the combined administration of 9-cis RA and Br lowered the steady-state level of the ACTH precursor proopiomelanocortin (POMC) more efficiently than either of the drugs alone. In conclusion, the effects of a combination of 9-cis RA and Br on ACTH synthesis/secretion and cell viability in AtT20, and on POMC transcriptional activity in human corticotropinomas might represent a suitable starting point for assessing the potential of this treatment regimen for ACTH-secreting pituitary adenomas. This study thus has potentially important implications for novel therapeutic approaches to CD.
authors.affiliation: Endocrinology Division, Departments of Medicine (G.O., D.R., N.M.A., F.C., S.F., C.S.) and Laboratory Medicine (C.C., M.P.), Academic Neurosurgery Unit (L.D.), Neuroscience Department, Padova University Hospital, 35128 Padova Italy; Neurosurgery Division (M.S.), Padova University Hospital, 35128 Padova, Italy; Neuroendocrinology Research Laboratory (M.F.C., F.P.G.), Istituto Auxologico Italiano Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20149 Milan, Italy; Department of Clinical Sciences and Community Health (G.M., F.P.-G.), University of Milan; Endocrinology and Diabetology Unit (G.M.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; and Clinical Neuroendocrinology (G.K.S., M.P.-P.), Department of Clinical Research, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Occhi
authors.forename: Daniela
authors.initials: D
authors.lastname: Regazzo
authors.forename: Nora Maria
authors.initials: NM
authors.lastname: Albiger
authors.forename: Filippo
authors.initials: F
authors.lastname: Ceccato
authors.forename: Sergio
authors.initials: S
authors.lastname: Ferasin
authors.forename: Massimo
authors.initials: M
authors.lastname: Scanarini
authors.forename: Luca
authors.initials: L
authors.lastname: Denaro
authors.forename: Chiara
authors.initials: C
authors.lastname: Cosma
authors.forename: Mario
authors.initials: M
authors.lastname: Plebani
authors.forename: Maria Francesca
authors.initials: MF
authors.lastname: Cassarino
authors.forename: Giovanna
authors.initials: G
authors.lastname: Mantovani
authors.forename: Günter K
authors.initials: GK
authors.lastname: Stalla
authors.forename: Francesca
authors.initials: F
authors.lastname: Pecori Giraldi
authors.forename: Marcelo
authors.initials: M
authors.lastname: Paez-Pareda
authors.forename: Carla
authors.initials: C
authors.lastname: Scaroni
mesh_terms: D000293:Adolescent; D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000328:Adult; D000818:Animals; D049109:Cell Proliferation; D054338:Cell Transdifferentiation; D052680:Corticotrophs / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D008297:Male; D052717:Melanotrophs / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D008954:Models, Biological; D047748:Pituitary ACTH Hypersecretion / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D011401:Promoter Regions, Genetic; D017448:Receptors, Dopamine D2 / Q000235:genetics* / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism*; D015854:Up-Regulation; D055815:Young Adult
chemical_list: C581293:DRD2 protein, human; D017448:Receptors, Dopamine D2; D014212:Tretinoin; D000324:Adrenocorticotropic Hormone