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Pancreatic neuroendocrine tumors (Pan-NETs), are heterogeneous neoplasms, whose incidence and prevalence are increasing worldwide. Pan-NETs are characterized by the expression of somatostatin receptors (SSTs). In particular, SST2 is the most widely distributed SST in NETs, thus representing the main molecular target for somatostatin analogs (SSAs). SSAs are currently approved for the treatment of well-differentiated NETs, and radionuclide-labeled SSAs are used for diagnostic and treatment purposes. SSAs, by binding to SSTs, have been shown to inhibit hormone secretion and thus provide control of hypersecretion symptoms, when present, and inhibit tumor proliferation. After SSA binding to SST2, the fate of the receptor is determined by trafficking mechanisms, crucial for the response to endogenous or pharmacological ligands. Although SST2 acts mostly through G protein-dependent mechanism, receptor-ligand complex endocytosis and receptor trafficking further regulate its function. SST2 mediates the decrease of hormone secretion via a G protein-dependent mechanism, culminating with the inhibition of adenylyl cyclase and calcium channels; it also inhibits cell proliferation and increases apoptosis through the modulation of protein tyrosine phosphatases. Moreover, SST2 inhibits angiogenesis and cell migration. In this respect, the cross-talk between SST2 and its interacting proteins, including Filamin A (FLNA) and aryl hydrocarbon receptor-interacting protein (AIP), plays a crucial role for SST2 signaling and responsiveness to SSAs. This review will focus on recent studies from our and other groups that have investigated the trafficking and signaling of SST2 in Pan-NETs, in order to provide insights into the mechanisms underlying tumor responsiveness to pharmacological treatments. • SST2 is the most widely distributed SST in NETs and the main molecular target for somatostatin analogs (SSAs). • SSAs are currently approved for the treatment of well-differentiated NETs. • Radionuclide-labeled SSAs are used for diagnostic and treatment purposes. • The fate of SST2 is determined by trafficking mechanisms, crucial for the response to ligands. • The cross-talk between SST2 and its interacting proteins plays a crucial role for SST2 signaling and responsiveness to SSAs. [ABSTRACT FROM AUTHOR]

The antidiabetic drug metformin displays anticancer properties in several neoplasms. In pituitary NETs, aryl hydrocarbon receptor-interacting protein (AIP) is up-regulated by the somatostatin analog octreotide. Metformin inhibited QGP-1 cell proliferation in a dose- and time-dependent manner, at concentrations similar to those achievable in treated patients (−31 ± 12%, p < 0.05 vs basal at 100 μM). Moreover, metformin decreased pancreatic neuroendocrine tumors (PAN-NETs) cell proliferation (−62 ± 15%, p < 0.0001 vs basal at 10 mM), without any additive effect when combined with octreotide. Both octreotide and metformin induced AIP up-regulation. AIP silencing abolished the reduction of mTOR phosphorylation induced by metformin and octreotide. Moreover, metformin decreased HSP70, increased Zac1 and AhR expression; these effects were abolished in AIP silenced QGP-1 cells. In conclusion, metformin acts as an anticancer agent in PAN-NET cells, its activity is mediated by AIP and its interacting proteins. These findings provide a novel insight into the antitumorigenic mechanism of metformin. • Metformin acts as an anticancer agent in PAN-NET cells. • AIP interacts with HSP70, AHR and Zac1. • Metformin action is mediated by AIP and its interacting proteins. [ABSTRACT FROM AUTHOR]