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AGONIST BIASED SIGNALING AT THE SST2A RECEPTOR: THE PAN-SOMATOSTATIN ANALOGS KE108 AND SOM230 ACTIVATE AND ANTAGONIZE DISTINCT SIGNALING PATHWAYS

Cescato, Renzo and Loesch, Kimberly A and Waser, Beatrice and Mäcke, Helmut R and Rivier, Jean E and Reubi, Jean Claude and Schonbrunn, Agnes and Imark, Esther (2010) AGONIST BIASED SIGNALING AT THE SST2A RECEPTOR: THE PAN-SOMATOSTATIN ANALOGS KE108 AND SOM230 ACTIVATE AND ANTAGONIZE DISTINCT SIGNALING PATHWAYS. Molecular Endocrinology, 24 (1). pp. 240-249. ISSN 0888-8809

Abstract

Somatostatin analogs that activate the sst2A receptor are used to treat neuroendocrine cancers because they inhibit tumor secretion and growth. Recently, new analogs capable of activating multiple somatostatin receptor subtypes have been developed in order to increase tumor responsiveness. We tested two such pan somatostatin analogs for functional selectivity at the sst2A receptor: SOM230, which activates sst1, sst2, sst3 and sst5 receptors, and KE108, which activates all sst receptor subtypes. Both compounds are reported to act as full agonists at their target sst receptors. In sst2A expressing HEK293 cells, somatostatin inhibited cAMP
production, stimulated intracellular calcium accumulation, and increased ERK phosphorylation. SOM230 and KE108 were also potent inhibitors of cAMP accumulation, as expected. However, they antagonized somatostatin stimulation of intracellular calcium and behaved as partial agonists/ antagonists for ERK phosphorylation. In pancreatic AR42J cells, which express sst2A receptors endogenously, SOM230 and KE108 were both full agonists for cAMP inhibition. However, although somatostatin increased intracellular calcium and ERK phosphorylation, SOM230 and KE108 again antagonized these effects. Distinct mechanisms were involved in sst2A receptor signaling in AR42J cells: pertussis toxin pretreatment blocked somatostatin inhibition of cAMP accumulation but not the stimulation of intracellular calcium and ERK phosphorylation. Our results demonstrate that SOM230 and KE108 behave as agonists for inhibition of adenylyl cyclase but antagonize somatostatin’s actions on intracellular calcium and ERK phosphorylation. Thus, SOM230 and KE108 are not somatostatin mimics and their functional selectivity at sst2A receptors must be considered in clinical applications where it may have important consequences for therapy.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); On institutional repository, PubMed Central, UK PubMed Central and PubMed Central International; Publisher's version/PDF cannot be used
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/1897

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