Differential regulation of human dopamine D2 and somatostatin receptor subtype expression by glucocorticoids in vitro
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 D2or 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 D2and 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, sst2mRNA was strongly down-regulated in a dose-dependentmanner (IC500.84 nM and 0.16 nM), whereas sst5 and especially D2 were much more resistant to DEX treatment. Sst2down-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. Pretreatment with DEX abrogated calcitonin inhibition by sst2-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 sst2, but not D2and only to aminor degree sst5in human neuro-endocrine BON and TT cells. This mechanism may also be responsible for the low expression of sst2in corticotroph adenomas and underwrite the current interest in sst5and D2as possible therapeutic targets for a medical treatment of Cushing's disease.
|Persistent URL||dx.doi.org/10.1677/JME-08-0110, hdl.handle.net/1765/25409|
de Bruin, C., Feelders, R.A., Waaijers, A.M., van Koetsveld, P.M., Sprij-Mooij, D., Lamberts, S.W.J., & Hofland, L.J.. (2009). Differential regulation of human dopamine D2 and somatostatin receptor subtype expression by glucocorticoids in vitro. Journal of Molecular Endocrinology, 42(1), 47–56. doi:10.1677/JME-08-0110