ß-arrestin expression in corticotroph tumor cells is modulated by glucocorticoids.

Pituitary-directed medical treatment for Cushing's disease (CD) is currently represented by membrane receptor targeting drugs (somatostatin analogs and dopamine agonists). Somatostatin and dopamine receptors are regulated by ß-arrestins, which have been shown to be differentially regulated by glucocorticoids in non-neuroendocrine cells. In this study we investigated the effects of glucocorticoids on ß-arrestin expression in corticotroph tumor cells. First, AtT20 cells, a mouse model of CD, were exposed to dexamethasone (Dex) at different time points and ß-arrestin expression was evaluated at mRNA and protein levels. Futhermore, ß-arrestin mRNA expression was evaluated in 17 human corticotroph adenoma samples and correlated to patients' pre-operative cortisol levels. We observed that Dex treatment induced a time-dependent increase in ß-arrestin 1 mRNA expression and a decrease in ß-arrestin 2. The same modulation pattern was observed at protein level. Dex-mediated modulation of ß-arrestins was abolished by co-treatment with mifepristone, and Dex withdrawal restored ß-arrestin expression to basal levels after 72 h. The evaluation of ß-arrestin mRNA in corticotroph adenomas from CD patients with variable disease activity showed a significant positive correlation between ß-arrestin 1 mRNA and urinary cortisol levels. The effect of glucocorticoids on ß-arrestin levels was confirmed by the analysis of two samples from a single patient, which underwent adenomectomy twice, with different pre-operative cortisol levels. In conclusion, glucocorticoids induce an inverse modulation of the two ß-arrestin isofoms in corticotroph tumor cells. Since ß-arrestins regulate membrane receptor functions, this finding may help to better understand the variable response to pituitary-targeting drugs in patients with Cushing's disease.

Cell specific interaction of pasireotide: review of preclinical studies in somatotroph and corticotroph pituitary cells.

BACKGROUND: Pasireotide is a second-generation somatostatin (SRIF) receptor ligand (SRL), approved for medical treatment of acromegaly and Cushing's disease (CD). The molecule is a stable cyclohexapeptide synthetized based on SRIF structure. Differently from first-generation SRLs (e.g. octreotide), preferentially binding somatostatin receptor (SST) subtype 2 (SST2), pasireotide has high affinity for multiple SSTs (SST5 > SST2 > SST3 > SST1). Interestingly, early preclinical studies demonstrated that pasireotide shows distinct functional properties compared to SRIF and first-generation SRLs when binding SSTs. METHODS: We aimed to highlight the differential receptor-targeted action of pasireotide in the treatment of somatotroph and corticotroph adenomas, throughout the critical revision of preclinical studies carried out on acromegaly and CD models. RESULTS: Different authors demonstrated that the antisecretory effect of pasireotide in somatotroph adenoma cell cultures is comparable to that of the SST2-preferential agonist octreotide. Some reports even show a direct correlation between SST2 mRNA expression and GH reduction after pasireotide treatment, thus laying for a predominant role of SST2 in driving pasireotide efficacy in somatotropinomas in vitro. On the other hand, the inhibitory effect of pasireotide on ACTH secretion in corticotropinoma cells seems to be mainly mediated by SST5. Indeed, most reports show a higher potency and efficacy of pasireotide compared to SST2 preferential agonists, while functional studies confirm the pivotal role of SST5 targeting in corticotroph cells. CONCLUSIONS: The analysis of preclinical studies carried out in somatotroph and corticoph adenomas points out that pasireotide shows a cell-specific activity, exerting its biological effects via different SSTs in the different adenoma histotypes.