Quantitative and functional expression of somatostatin receptor subtypes in human prolactinomas

Recently, it was demonstrated that somatostatin analogs preferential for the SSTR5 subtype suppress PRL release from prolactinoma cell cultures by 30-40%. These data supported the idea of somatostatin receptor subtype-specific control of PRL secretion in such tumors. The present study examines the quantitative profile of SSTRs messenger ribonucleic acid (mRNA) in 10 PRL-secreting tumors and correlates the expression with the ability of native somatostatins (SS14 and SS28), SSTR2 preferential analogs (octreotide and BIM-23197), and the SSTR5 preferential analog BIM-23268 to suppress PRL secretion. RT-PCR quantitative analysis showed a large predominance of SSTR5 mRNA [5648 +/- 1918 pg/pg glyceraldehyde-3-phosphate dehydrogenase (GAPDH)] vs. SSTR2 mRNA (148 +/- 83 pg/pg GAPDH). The SSTR1 transcript was also highly expressed in prolactinomas (1296 +/- 669 pg/pg GAPDH). SSTR5 mRNA expression correlated with PRL inhibition induced by both SRIF14 and SRIF28. Among the different analogs tested, only BIM-23268 produced inhibition of PRL release similar to that achieved with the native peptides. Its EC50 for PRL suppression was 0.28 +/- 0.10 nmol/L. No additive effects on PRL suppression were achieved by cotreatment of the tumor cells with SSTR2 and SSTR5 preferential analogs. In the same tumor cell cultures, quinagolide, a potent dopamine agonist, produced a dose-dependent inhibition of PRL with an EC50 at least 10 times lower than that of BIM-23268. Coincubation of quinagolide and BIM-23268, particularly in tumor cells resistant to dopamine agonist treatment, did not produce additive effects on PRL suppression. In conclusion, prolactinomas have a specific pattern of SSTR subtype mRNA expression (SSTR5 and SSTR1). SSTR5 expression is correlated to PRL regulation. These inhibitory effects are superimposable, at a higher concentration, to those of the dopamine agonists, but are not additive, particularly in the adenomas resistant to dopaminergic suppression of PRL release.