The impact of SST2 trafficking and signaling in the treatment of pancreatic neuroendocrine tumors.
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.
['Vitali|E|E|', 'Piccini|S|S|', 'Trivellin|G|G|', 'Smiroldo|V|V|', 'Lavezzi|E|E|', 'Zerbi|A|A|', 'Pepe|G|G|', 'Lania|A G|AG|']
D017209:Apoptosis D002465:Cell Movement D049109:Cell Proliferation D006801:Humans D009363:Neoplasm Proteins D009389:Neovascularization, Pathologic D018358:Neuroendocrine Tumors D010190:Pancreatic Neoplasms D017481:Receptors, Somatostatin D015398:Signal Transduction
SST2 Pan-NETs Somatostatin analogs Filamin A AIP