SOMATOSTATIN ACTS BY INHIBITING THE CYCLIC-3',5'-ADENOSINE-MONOPHOSPHATE (CAMP) PROTEIN-KINASE-A PATHWAY, CAMP RESPONSE ELEMENT-BINDING PROTEIN (CREB) PHOSPHORYLATION, AND CREB TRANSCRIPTION POTENCY

Somatostatin (SRIF) was discovered as an inhibitor of GH secretion fro m pituitary somatotroph cells. SRIF analogs are very effective agents used to treat neuroendocrine tumors and are now being used with increa sing frequency in clinical trials to treat more aggressive malignancie s. However, the cellular components mediating SRIF signal transduction remain largely unknown. We have stably overexpressed the SRIF type 2 receptor (SST2) in GH(4) rat somatomammotroph cells, establishing a ph ysiologically relevant model system. In this model, the SRIF analog, B IM23014, inhibited forskolin-induced cAMP accumulation, protein kinase A activation, cAMP response element-binding protein phosphorylation, and Pit-1/GHF-1 promoter activation in an okadaic acid-insensitive man ner. Pertussis toxin inhibited the effects of BIM23014, documenting th at SST2 signaling was coupled to G(i). Moreover, the inhibitory effect s of BIM23014 were reversed by overexpression of protein kinase A cata lytic subunit, indicating that SRIF does not act via serine/threonine phosphatases, but, rather, by lowering protein kinase A activity. Thes e data define the components of the SRIF/SST2 receptor signaling pathw ay and provide important mechanistic insights into how SRIF controls n euroendocrine tumors. As SRIF analogs are effective antitumor agents, and many other related compounds are in development, the knowledge gai ned here will further our understanding of their mechanism of action i n other malignancies as well.