9-CYS RETINOIC ACID INCRESEAS AtT20 SENSITIVITY TO DOPAMINE AGONISTS BY UPREGULATING DOPAMINE RECEPTOR TYPE-2: A POSSIBLE NOVEL MEDICAL APPROACH FOR CUSHING'S DISEASE?

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 163-194-Pituitary Disorders & Case Reports
Basic/Clinical
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-189
Daniela Regazzo, Nora Maria Albiger, Filippo Ceccato, Sara Mazzocut, Franco Mantero, Carla Maria Scaroni and Gianluca Occhi*
University of Padova, Padova, Italy
Introduction

Retinoic acid (RA) is recognized to reduce ACTH secretion in pituitary corticotropinomas by activating the nuclear receptors RAR and RXR.

Similarly dopamine agonists (DA) inhibit ACTH secretion in corticotroph-secreting adenomas depending on Dopamine Receptor Type 2 (DRD2) expression. Satisfactory results have however been obtained only in a minority of patients with escape usually observed after prolonged therapy. Recently RA responsive elements have been described in the DRD2 promoter so that it would be useful to investigate wherever RA induces DRD2 expression in corticotropinomas.

Methods & Materials

The ACTH-secreting AtT20 cell line was transfected with a vector containing the luciferase gene under control of DRD2 promoter (DRD2). A dose-dependent curve was established after 24h 9-cis RA treatment. To confirm the direct effect of 9-cis RA on DRD2 expression, cells were cotransfected with either SMRT or N-CoR expressing vectors that are known to inhibit the RA pathway. The effect of DA and RA cotreatment on cell viability was evaluated by MTT while those on POMC transcriptional activity by qPCR.

Results

Att20 cells transfected with DRD2R-Luc and treated with increasing concentrations of 9-cis RA showed a dose-dependent increase of luciferase expression (1.5- and 3-fold increase at 0,1uM and 1 uM respectively). By cotransfecting with either SMRT or N-CoR we observed the loss of ability of DRD2 promoter to respond to 9-cis RA confirming that such effect is directly mediated by the activation of the RA pathway. MTT test and qPCR experiments revealed that in the DRD2 expressing AtT20 the co-treatment reduce cell viability and POMC transcriptional activity more than 9-cis RA or DA treatment alone.

Conclusion

DRD2 expression is increased through the activation of the RA pathway making AtT20 cells more sensitive to dopamine agonists. These data suggest that 9-cis RA could be applied to enhance ACTH-secreting pituitary tumors sensitivity and responsiveness to DA.

The information obtained by these studies could be important also for other diseases where DA are useful, e.g.. DA-resistant prolactinomas or Parkinson’ disease, diabetes mellitus and metabolic syndrome.

Nothing to Disclose: DR, NMA, FC, SM, FM, CMS, GO

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm