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.

Sexual Dimorphism in Cellular and Molecular Features in Human ACTH-Secreting Pituitary Adenomas

“…As regards ACTH synthesis, we did not observe differences in POMC expression between maleand female-excised adenomas both in unchallenged wells and after CRH/dexamethasone incubation. This finding is in line with the lack of correlation between POMC and ACTH in corticotrope adenomas in vitro [53,54] and, in the present setting, suggests that sexual dimorphism affects POMC peptide processing and secretion rather than POMC transcription.…”

The GIP/GIPR axis is functionally linked to GH-secretion increase in a significant proportion of gsp− somatotropinomas

“…A second fragment for each tissue specimen was immersed in RNAlater (Ambion), kept at 4°C for 24 h and then stored at −20°C until RNA extraction. The remainder of each somatotropinoma was transferred to sterile cold complete culture medium and processed within 36 h as previously described (13). Informed consent was obtained from each patient.…”

Pituitary Hyperplasia, Hormonal Changes and Prolactinoma Development in Males Exposed to Estrogens—An Insight From Translational Studies

“…Interestingly, these authors reported mRNA and protein expression of retinoic-acid-synthesizing enzyme aldehyde dehydrogenase 1A1 (ALDH1A1 or RALDH1), only in lactotropic cells from males but not from females, and in folliculo-stellate cells (FS) from both sexes [16]. This enzyme catalyzes the conversion of 9-cis-retinal to 9-cis-retinoic acid, which increases the expression of dopamine receptor type 2 (DR2) in normal and pituitary tumors [63,64]. In line with this, promotion of lactotropic cell secretion and proliferation in adults is associated with reduced expression of retinoic-acid-synthesizing enzyme ALDH1, indicating its involvement in this process.…”