Differential regulation of human dopamine D-2 and somatostatin receptor subtype expression by glucocorticoids in vitro

Christiaan Bruin, R.A. Feelders, Marlijn Waaijers, Peter van Koetsveld, Diana Mooij, S.W.J. Lamberts, Leo Hofland

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Abstract

Dopamine agonists (DA) and somatostatin (SS) analogues have been proposed in the treatment of ACTH-producing neuroendocrine tumours that cause Cushing's syndrome. Inversely, glucocorticoids (GCs) can differentially influence DA receptor D-2 or SS 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 D-2 and sst expression in three human neuro-endocrine cell lines: BON (carcinoid) and 17 (medullary thyroid carcinoma) versus DMS (small cell lung cancer), which is severely GC resistant. In BON and TT, sst(2) mRNA was strongly down-regulated in a dose-dependent manner (IC50 0.84 nM and 0.16 nM), whereas sst(5) and especially D-2 were much more resistant to DEX treatment. Sst(2) 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 sst(2)-specific(-42%) binding sites. Pretreatment with DEX abrogated calcitonin inhibition by sst(2)-preferring analogue octreotide in TT. In DMS, DEX did not cause significant changes in the expression of these receptor subtypes. In conclusion, we show that GCs selectively down-regulate sst(2), but not D-2 and only to a minor degree sst(5) inhuman neuro-endocrine BON and TT cells. This mechanism may also be responsible for the low expression of sst(2) in corticotroph adenomas and underwrite the current interest in sst(5) and D-2 as possible therapeutic targets for a medical treatment of Cushing's disease.
Original languageUndefined/Unknown
Pages (from-to)47-56
Number of pages10
JournalJournal of Molecular Endocrinology
Volume42
Issue number1-2
DOIs
Publication statusPublished - 2009

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  • EMC MM-01-39-01

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