The Role of Receptor-Ligand Interaction in Somatostatin Signaling Pathways: Implications for Neuroendocrine Tumors

Abstract

Neuroendocrine tumors (NETs) arise from neuroendocrine cells and manifest in diverse organs. Key players in their regulation are somatostatin and its receptors (SSTR1-SSTR5). Understanding receptor-ligand interactions and signaling pathways is vital for elucidating their role in tumor development and therapeutic potential. This review highlights SSTR characteristics, localization, and expression in tissues, impacting physiological functions. Mechanisms of somatostatin and synthetic analogue binding to SSTRs, their selectivity, and their affinity were analyzed. Upon activation, somatostatin initiates intricate intracellular signaling, involving cAMP, PLC, and MAP kinases and influencing growth, differentiation, survival, and hormone secretion in NETs. This review explores SSTR expression in different tumor types, examining receptor activation effects on cancer cells. SSTRs' significance as therapeutic targets is discussed. Additionally, somatostatin and analogues' role in hormone secretion regulation, tumor growth, and survival is emphasized, presenting relevant therapeutic examples. In conclusion, this review advances the knowledge of receptor-ligand interactions and signaling pathways in somatostatin receptors, with potential for improved neuroendocrine tumor treatments.

Keywords: SSTR characteristics; hormone secretion regulation; intracellular signaling; neuroendocrine tumors; receptor–ligand interactions; therapeutic targets; tumor development mechanisms.

Figure 1

Mechanism of the antitumor effect of SST receptors after ligand binding. This mechanism involves several key signaling pathways: (1) Adenylate cyclase pathway: SSTR binds to adenylate cyclase and reduces levels of cyclic adenosine monophosphate (cAMP) in the cell. Reducing the concentration of cAMP leads to the inhibition of protein kinase activity, which in turn prevents the activation of oncogenes and inhibits the development and progression of the tumor. (2) Tyrosine protein pathway: SSTR binds to SST, leading to an increase in protein tyrosine phosphatase (PTP), which dephosphorylates and inactivates tyrosine kinase. Many protein kinases can be inhibited, such as mitogen-activated protein kinase (MAPK), leading to inhibition of DNA and protein synthesis. (3) Phosphatidylinositol 3 kinase (PI3K) pathway: SSTR increases the expression of p21 and p27 via PI3K, resulting in the inhibition of phosphorylation of PRb and the cyclin E-dependent kinase 2 complex. (4) Calcium signaling pathway: SSTR causes an ion exchange between Ca²⁺ and H⁺, which causes a decrease in the concentration of intracellular calcium, an increase in acidification of the intracellular environment and inhibition of cell proliferation.