Somatostatin receptor sst2 gene transfer in human prolactinomas in vitro: impact on sensitivity to dopamine, somatostatin and dopastatin, in the control of prolactin secretion.

Abstract

OBJECTIVE:

As prolactinomas fail to respond to dopamine agonist (DA) in 10-20% of cases, we hypothesized that somatostatin subtype 2 receptor (sst2) overexpression in DA-resistant prolactinomas may enhance suppression of prolactine (PRL) using chimeric agonist (dopastatin) that simultaneously binds sst2 and the dopamine subtype 2 receptor (D2DR).

DESIGN AND METHODS:

PRL suppression by octreotide, sst5 agonist, sst2-D2DR agonist (BIM-23A760 dopastatin) and cabergoline was assessed in primary cultures of seven DA-resistant prolactinomas overexpressing sst2.

RESULTS:

sst2 was effectively overexpressed via adenoviral expression in prolactinomas (38.1±7.4 vs. 0.1±0.1 copy/copy β-Gus) and induced octreotide sst2-mediated PRL suppression that remained lower than that induced by DA. BIM-23A760 inhibited PRL similarly to cabergoline both in the control and sst2-expressing cells. Antagonist experiments confirmed predominant dopaminergic effect in dopastatin activity.

CONCLUSION:

sst2 was successfully overexpressed in prolactinomas. However BIM-23A760 was unable to enhance PRL suppression underlining a predominant dopaminergic contribution in its action.

• Authors: Thomas Cuny, Amira Mohamed, Thomas Graillon, Catherine Roche, Céline Defilles, Anne-Laure Germanetti, Bettina Couderc, Dominique Figarella-Branger, Alain Enjalbert, Anne Barlier, Alexandru Saveanu
• Journal: Molecular and cellular endocrinology (Mol Cell Endocrinol) Vol. 355 Issue 1 Pg. 106-13 (May 15 2012) ISSN: 1872-8057 [Electronic] Ireland
• PMID: 22348806 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Dopamine Agonists
• Ergolines
• Receptors, Dopamine D2
• Receptors, Somatostatin
• Somatostatin
• Prolactin
• TBR-760
• Cabergoline
• Octreotide
• Dopamine

Topics

• Adenoviridae
• Adolescent
• Adult
• Cabergoline
• Dopamine (analogs & derivatives, metabolism, pharmacology)
• Dopamine Agonists (pharmacology)
• Ergolines (pharmacology)
• Female
• Genetic Vectors
• Humans
• Male
• Octreotide (pharmacology)
• Pituitary Neoplasms (drug therapy, metabolism, pathology)
• Primary Cell Culture
• Prolactin (antagonists & inhibitors, genetics)
• Prolactinoma (drug therapy, metabolism, pathology)
• Receptors, Dopamine D2 (metabolism)
• Receptors, Somatostatin (genetics, metabolism)
• Somatostatin (analogs & derivatives, pharmacology)
• Transfection