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

Gianluca Occhi, Daniela Regazzo, Nora Maria Albiger, Filippo Ceccato, Sergio Ferasin, Massimo Scanarini, Luca Denaro, Chiara Cosma, Mario Plebani, Maria Francesca Cassarino, Giovanna Mantovani, Günter K. Stalla, Francesca Pecori Giraldi, Marcelo Paez-Pareda, Carla Scaroni

Research output: Contribution to journalArticle

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,anda 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 theDAbromocriptine (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-cisRAand 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. Copyright

Original languageEnglish
Pages (from-to)3538-3549
Number of pages12
JournalEndocrinology
Volume155
Issue number9
DOIs
Publication statusPublished - Sep 1 2014

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Melanotrophs
Corticotrophs
Pituitary ACTH Hypersecretion
Dopamine Receptors
Adrenocorticotropic Hormone
Cell Proliferation
ACTH-Secreting Pituitary Adenoma
Pro-Opiomelanocortin
Pituitary Neoplasms
Tretinoin
Cell Survival
Dopamine Agonists
Therapeutics
Human Activities
alitretinoin
Morbidity
Cell Line
Mortality
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Endocrinology

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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. / Occhi, Gianluca; Regazzo, Daniela; Albiger, Nora Maria; Ceccato, Filippo; Ferasin, Sergio; Scanarini, Massimo; Denaro, Luca; Cosma, Chiara; Plebani, Mario; Cassarino, Maria Francesca; Mantovani, Giovanna; Stalla, Günter K.; Giraldi, Francesca Pecori; Paez-Pareda, Marcelo; Scaroni, Carla.

In: Endocrinology, Vol. 155, No. 9, 01.09.2014, p. 3538-3549.

Research output: Contribution to journalArticle

Occhi, Gianluca ; Regazzo, Daniela ; Albiger, Nora Maria ; Ceccato, Filippo ; Ferasin, Sergio ; Scanarini, Massimo ; Denaro, Luca ; Cosma, Chiara ; Plebani, Mario ; Cassarino, Maria Francesca ; Mantovani, Giovanna ; Stalla, Günter K. ; Giraldi, Francesca Pecori ; Paez-Pareda, Marcelo ; Scaroni, Carla. / 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. In: Endocrinology. 2014 ; Vol. 155, No. 9. pp. 3538-3549.
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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,anda 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 theDAbromocriptine (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-cisRAand 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. Copyright",
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T1 - 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

AU - Occhi, Gianluca

AU - Regazzo, Daniela

AU - Albiger, Nora Maria

AU - Ceccato, Filippo

AU - Ferasin, Sergio

AU - Scanarini, Massimo

AU - Denaro, Luca

AU - Cosma, Chiara

AU - Plebani, Mario

AU - Cassarino, Maria Francesca

AU - Mantovani, Giovanna

AU - Stalla, Günter K.

AU - Giraldi, Francesca Pecori

AU - Paez-Pareda, Marcelo

AU - Scaroni, Carla

PY - 2014/9/1

Y1 - 2014/9/1

N2 - 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,anda 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 theDAbromocriptine (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-cisRAand 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. Copyright

AB - 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,anda 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 theDAbromocriptine (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-cisRAand 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. Copyright

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