Peptide Receptor Targeting in Cancer: The Somatostatin Paradigm

Figure 1

Schematic representation of the intracellular signaling pathways modulated by somatostatin receptors. Antiproliferative effects of somatostatin (SST) and its analogs; SST and analogs binding to SST receptors activate different phosphotyrosine phosphatases (PTPs) SHP-1 and SHP-2 and PTPη. Activated SHP-1 triggers intracellular proapoptoptic signals involving the induction of caspase activation and p53/Bax. SHP-1 also cause apoptosis by activation of the transcription factor NF-κB leading to the inhibition of the MAP kinase JNK anti-apoptotic effects. SHP-2 activates Src that directly interacts with PTPη inducing its phosphorylation in tyrosine and activation. PTPη dephosphorylates intracellular effectors involved in the control of cell cycle progression, such as the ERK and the PI3K/Akt pathways, causing the upregulation of the cyclin kinase inhibitors p21^cip1/waf1 and p27^kip1 and the tumor suppressor gene Zac1. As a result, cells accumulate in G1 phase without entering S-phase and cell proliferation is blocked. Antisecretory effects of SST and its analogs; SST inhibits the secretion/synthesis of many hormones through the inhibition of voltage-dependent Ca²⁺ channels and activation of K⁺ channels, decreasing intracellular Ca²⁺ concentration, and inhibition of adenylyl cyclase, lowering intracellular cAMP levels. Activated pathway: green arrows; inhibited pathway: red arrows.