Somatostatin (SS), SS receptors and SS analog treatment in tumorigenesis

Abstract

Somatostatin (SS) is an inhibitory tetradecapeptide hormone with exocrine, endocrine, paracrine, and autocrine activities, which plays an important regulatory role in several cell functions, including inhibition of endocrine secretion and cell proliferation. Most of the effects of SS and of its currently available analogs are mediated via five different G proteincoupled receptor (GPCRs), codenamed sst [1][2][3][4][5] . SS receptors (sst s ) are expressed in a tissue-and subtypeselective manner in both normal and neoplastic cells, and the majority of SS target tissues express multiple sst s . Recent data suggest that when sst s are coexpressed, they may interact forming homo-and hetero-dimers also with other GPCRs, thus altering their original pharmacological and functional profiles. The formation of dimers can be not only constitutive, but also ligandpromoted: hence, compounds with high affinity for the different receptor subtypes can be used to achieve effects elicited by specific dimers. A feature common to most GPCRs is the cyclic process of signaling, desensitization, internalization, resensitization, and recycling to the plasma membrane. These events prevent cells from undergoing excessive receptor stimulation or periods of prolonged inactivity. SS receptors differently internalize after agonist binding and, specifically, sst 2 , sst 3 and sst 5 are internalized to a greater extent than sst 1 or sst 4 . sst s are linked to several second messenger systems which are involved in their downstream intracellular response (i.e., adenylyl cyclase, calcium and potassium ion channels, Na + /H + antiporter, phospholipase C, phospholipase A2, mitogen activated protein kinase, NO/cGMP, and serine-, threonine, and phosphotyrosyl-protein phosphatase). Interestingly, SS and SS analogs can control tumor development and progression/metastatization by direct actions, mediated by the sst s , and indirect actions, independent of receptor involvement. The direct antiproliferative effects include inhibition of autocrine/paracrine growth-promoting hormone/growth factor synthesis, arrest of cell division (by blockade of growth factor-mediated mitogenic signals), suppression of cell invasion and induction of apoptosis (programmed cell death). Indirect antitumor effects of SS include suppression of synthesis or/and release of growth factors and growth-promoting hormones, such as insulin, prolactin, insulin like-growth factor 1, epidermal growth factor, transforming growth factor-, gastrin, cholecystokinin and growth hormone. A specific pattern of sst s activation thus seems to elicit relevant antitumoral actions and deserves further exploitation with the aim of validating novel therapeutic approaches to cancer.