Somatostatin receptor ligands and resistance to treatment in pituitary adenomas

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   Figure 1

   Amino acid sequences of the two biologically active somatostatin (SST) forms, SST14 and SST28 (Brazeau et al. 1973), and other four somatostatin receptor ligands (Bauer et al. 1982, Taylor et al. 1988, Bruns et al. 2002, Shimon 2003).
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   Figure 2

   Hypercortisolemia in active Cushing's disease (CD) hampers ACTH suppression by somatostatin or SSTR2 receptor ligand treatment due to down-regulation of SSTR2 expression in corticotrope pituitary adenomas (de Bruin et al. 2009). Cortisol-mediated SSTR2 down-regulation in corticotrope adenomas is reversible after achieving eucortisolemia; use of SSTR2 receptor ligands may induce improved biochemical responsiveness (van der Pas et al. 2013).
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   Figure 3

   Schematic of the intracellular signaling pathways modulated by SSTR2 after somatostatin (SST) or SRLs action. From left to right, the antiproliferative pathway is activated through three different phosphotyrosine phosphatases (PTPs), SHP1, SHP2, and PTPη (Pan et al. 1992). SHP2 activates Src that directly interacts with PTPη inducing its phosphorylation and activation (Lopez et al. 1997). Then, Ras and Rap1-GTP inhibits the phosphatidylinositide-3-kinase (PI3K) target Akt. This, in turn, activates the MAPK pathway stimulating the ERK1/2, and also p38, which have as targets Elk1, and the activating transcription factor 2 (ATF2) (Sellers et al. 2000). In addition, the glycogen synthase kinase 3 (GSK3β) is phosphorylated and inhibited. The results are upregulation of p21^Cip1 and p27^Kip1, which will arrest cell cycle at the G1/S transition phase (Ben-Shlomo & Melmed 2010, Theodoropoulou et al. 2010). Activated SHP1 also triggers intracellular pro-apoptotic signals involving the induction of caspases activation and p53/Bax. GSK3β activates the tumor suppressor tuberin TSC2/TSC1 complex, which in turn inhibits the mammalian target of rapamycin (mTOR) also inducing cell apoptosis. Additionally, SHP1 associates with nitric oxide synthase (NOS) and dephosphorylates it, leading to NOS activation and nitric oxide (NO) production. NO activates soluble guanylate cyclase (GC), which converts GTP to cGMP. Increased cGMP inhibits cell growth (Ben-Shlomo & Melmed 2010). SST also induces ZAC1 expression through a mechanism involving Gαi, SHP1, GSK3β, and the Zac1 activator p53. Zac1 is capable of inducing apoptosis and cell cycle arrest (Theodoropoulou et al. 2010). Finally, SST has key anti-secretory effects increasing K⁺ efflux and membrane hyperpolarization, which in turn closes voltage-dependent Ca²⁺ channels decreasing intracellular Ca²⁺ influx and concentration. Adenylyl cyclase inhibition also lowers cAMP levels and PKA activity hampering hormone secretion (Patel et al. 1994). Activated pathway, black arrows; inhibited pathway, red arrows.
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   Figure 4

   Schematic of SSTR desensitization through mechanisms involving internalization and recycling, or receptor degradation. Internalization degree varies depending on SSTR type (Table 1). It also depends whether the stimuli is through SST or a different somatostatin receptor ligand (SRL) (Lesche et al. 2009). Recently, lower expression of the scaffold protein β-arrestin 1 correlated with less SSTR2 desensitization and improved SRL responsiveness in GH-secreting pituitary adenomas (Gatto et al. 2013).
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   Figure 5

   Schematic of the intracellular signaling pathways modulated by SSTR5 after somatostatin (SST) or SRLs action. In contrast to SSTR2, the antiproliferative mechanism is activated through PTP-independent pathways. After inhibition of adenylate cyclase by Gαi subunit activation, SSTR5 affects phospholipase C (PLC) which in turn cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) into diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). The latter is released into the cytosol, where it binds to its receptor (IP3R) at endoplasmic reticulum and release intracellular Ca²⁺ whereas DAG recruits and activates PKC, which in turn open voltage-gated Ca²⁺ channels. SSTR5 uses its inhibitory action on PLC and IP3 to inhibit intracellular release of Ca²⁺ as well as extracellular Ca²⁺ influx (Wilkinson et al. 1997). In addition, SSTR5 blocks cell proliferation inhibiting MAPK and c-fos (Cordelier et al. 1997). Activated pathway, black arrows; inhibited pathway, red arrows.

• © 2014 Society for Endocrinology