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C de Bruin, Internal Medicine, Erasmus MC, Rotterdam, 3015 CE, Netherlands
R Feelders, Internal Medicine, Erasmus MC, Rotterdam, Netherlands
M Waaijers, Internal Medicine, Erasmus MC, Rotterdam, Netherlands
P van Koetsveld, rotterdam, Netherlands
D Sprij-Mooij, Rotterdam, Netherlands
S Lamberts, Rotterdam, Netherlands
L Hofland, Rotterdam, Netherlands

Correspondence: Christiaan de Bruin, Email: c.debruin{at}erasmusmc.nl

Abstract

Dopamine agonists and somatostatin analogues have been proposed in the treatment of ACTH-producing neuro-endocrine tumours that cause Cushing’s syndrome. Inversely, glucocorticoids (GC) can differentially influence dopamine receptor D2 or somatostatin receptor subtype (sst) expression in rodent models. If this also occurs in human neuro-endocrine cells, then cortisol-lowering therapy could directly affect the expression of these target receptors. In this study we investigated the effects of the GC dexamethasone (DEX) on D2 and sst expression in three human neuro-endocrine cell lines: BON (carcinoid) and TT (medullary thyroid carcinoma) versus DMS (small cell lung cancer), which is severely GC-resistant. In BON and TT, sst2 mRNA was strongly down-regulated in a dose-dependent manner (IC50 0.84 nM and 0.16 nM), whereas sst5 and especially D2 were much more resistant to DEX-treatment. Sst2 down-regulation was abrogated by a GC receptor antagonist and reversible in time upon GC withdrawal. At the protein level, DEX also induced a decrease in the total number of SS (-52%) and sst2-specific (-42%) binding sites. Pre-treatment with DEX abrogated calcitonin-inhibition by sst2-preferring analogue octreotide in TT. In DMS, DEX did not cause significant changes in expression of these receptor subtypes. In conclusion, we show that GCs selectively down-regulate sst2, but not D2 and only to a minor degree sst5 in human neuro-endocrine BON and TT cells. This mechanism may also be responsible for the low expression of sst2 in corticotroph adenomas and underwrite the current interest in sst5 and D2 as possible therapeutic targets for a medical treatment of Cushing’s disease.

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				C. de Bruin, A. M. Pereira, R. A. Feelders, J. A. Romijn, F. Roelfsema, D. M. Sprij-Mooij, M. O. van Aken, A.-J. van der Lelij, W. W. de Herder, S. W. J. Lamberts, et al. Coexpression of Dopamine and Somatostatin Receptor Subtypes in Corticotroph Adenomas J. Clin. Endocrinol. Metab., April 1, 2009; 94(4): 1118 - 1124. [Abstract] [Full Text] [PDF]