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 neuro-endocrine 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 TT (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 (IC(50) 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) in human 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.
Division of Endocrinology, Department of Internal Medicine, Erasmus Medical Center, 's Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. c.debruin@erasmusmc.nl
C
C
de Bruin
R A
RA
Feelders
A M
AM
Waaijers
P M
PM
van Koetsveld
D M
DM
Sprij-Mooij
S W J
SW
Lamberts
L J
LJ
Hofland
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D053938:DNA Fragmentation; D003907:Dexamethasone / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D005938:Glucocorticoids / Q000378:metabolism*; D006727:Hormone Antagonists / Q000378:metabolism; D006801:Humans; D015735:Mifepristone / Q000378:metabolism; D015282:Octreotide / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011869:Radioligand Assay; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism*; D017481:Receptors, Somatostatin / Q000235:genetics / Q000378:metabolism*; D013004:Somatostatin / Q000378:metabolism
D018931:Antineoplastic Agents, Hormonal; D005938:Glucocorticoids; D006727:Hormone Antagonists; D020033:Protein Isoforms; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D017481:Receptors, Somatostatin; D015735:Mifepristone; D013004:Somatostatin; D003907:Dexamethasone; D015282:Octreotide; D004298:Dopamine