A Somatostatin Receptor Subtype-3 (SST3) Peptide Agonist Shows Antitumor Effects in Experimental Models of Nonfunctioning Pituitary Tumors.

PURPOSE: Somatostatin analogues (SSA) are efficacious and safe treatments for a variety of neuroendocrine tumors, especially pituitary neuroendocrine tumors (PitNET). Their therapeutic effects are mainly mediated by somatostatin receptors SST2 and SST5. Most SSAs, such as octreotide/lanreotide/pasireotide, are either nonselective or activate mainly SST2. However, nonfunctioning pituitary tumors (NFPTs), the most common PitNET type, mainly express SST3 and finding peptides that activate this particular somatostatin receptor has been very challenging. Therefore, the main objective of this study was to identify SST3-agonists and characterize their effects on experimental NFPT models. EXPERIMENTAL DESIGN: Binding to SSTs and cAMP level determinations were used to screen a peptide library and identify SST3-agonists. Key functional parameters (cell viability/caspase activity/chromogranin-A secretion/mRNA expression/intracellular signaling pathways) were assessed on NFPT primary cell cultures in response to SST3-agonists. Tumor growth was assessed in a preclinical PitNET mouse model treated with a SST3-agonist. RESULTS: We successfully identified the first SST3-agonist peptides. SST3-agonists lowered cell viability and chromogranin-A secretion, increased apoptosis in vitro, and reduced tumor growth in a preclinical PitNET model. As expected, inhibition of cell viability in response to SST3-agonists defined two NFPT populations: responsive and unresponsive, wherein responsive NFPTs expressed more SST3 than unresponsive NFPTs and exhibited a profound reduction of MAPK, PI3K-AKT/mTOR, and JAK/STAT signaling pathways upon SST3-agonist treatments. Concurrently, SSTR3 silencing increased cell viability in a subset of NFPTs. CONCLUSIONS: This study demonstrates that SST3-agonists activate signaling mechanisms that reduce NFPT cell viability and inhibit pituitary tumor growth in experimental models that expresses SST3, suggesting that targeting this receptor could be an efficacious treatment for NFPTs.

Dietary fat alters the expression of cortistatin and ghrelin systems in the PBMCs of elderly subjects: putative implications in the postprandial inflammatory response.

SCOPE: Dietary fat influences systemic inflammatory status, which determines the progression of age-associated diseases. Since somatostatin (SST), cortistatin (CORT), and ghrelin systems modulate inflammatory response, we aim to comprehensively characterize the presence and regulation of the components of these systems in the peripheral blood mononuclear cells (PMBCs), a subset of white blood cells placed at the crossroad between diet and inflammation, in response to diets with different fat composition, and during the postprandial phase in elderly subjects. METHODS AND RESULTS: The applied nutrigenomic, inflammation-related PBMC-based approach revealed that the majority of components of SST/CORT and ghrelin systems are present in the human PBMCs. Particularly, CORT, SST/CORT receptors (sst2, sst3, sst5, and sst5TMD4), ghrelin, its acylating enzyme (GOAT), In1-ghrelin variant, and GHSR1b were detected in PBMCs. Their expression was altered in the long-term by diet composition, and in the short-term, during the postprandial phase. Of particular relevance is the postprandial elevation of CORT, sst2, and sst5 expression in PBMCs of subjects under n-3 PUFAs-enriched diet. CONCLUSION: Our results suggest a potential relevant role of CORT/ssts and ghrelin systems in regulating PBMCs response to nutrient intake, which could help to explain the positive effects of n-3 PUFAs-enriched diets in reducing the inflammatory response.