Abstract
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. 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. 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. 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.
Highlights
Somatostatin receptors (SST1–5) comprise a family of seven transmembrane G-protein–coupled receptors able to bind and be activated by somatostatin [1, 2]
This study demonstrates that somatostatin receptor subtype-3 (SST3)-agonists activate signaling mechanisms that reduce nonfunctioning pituitary tumors (NFPTs) 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
Some neuroendocrine tumors (NET) types express SST3 at higher or similar levels than SST2 or SST5. This is the case for some gastroenteropancreatic NETs [5], pheochromocytomas [6] and specially nonfunctioning pituitary tumors (NFPTs), which represent a heterogeneous group of tumors that constitute 30% of all pituitary NETs (PitNET) [7,8,9,10]
Summary
Somatostatin receptors (SST1–5) comprise a family of seven transmembrane G-protein–coupled receptors able to bind and be activated by somatostatin [1, 2]. Available somatostatin analogues (octreotide/lanreotide/pasireotide) are used to treat neuroendocrine tumors (NET), including pituitary NETs (PitNET), where they reduce/normalize hormonal levels, shrink tumors, and improve clinical symptoms [1, 4]. Most of their therapeutic actions are assumed to be mediated through SST2 and SST5 activation [1]. Some NETs types express SST3 at higher or similar levels than SST2 or SST5 This is the case for some gastroenteropancreatic NETs [5], pheochromocytomas [6] and specially nonfunctioning pituitary tumors (NFPTs), which represent a heterogeneous group of tumors that constitute 30% of all PitNETs [7,8,9,10]
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