Endocrine Abstracts (2011) 26 S3.2

A new truncated variant of somatostatin receptor subtype five, sst5TMD4, is present in pituitary tumours and breast cancer, and impairs the normal response to somatostatin

Justo P Castaño, Manuel D Gahete, José Córdoba-Chacón, Antonio J Martinez-Fuentes, Laura M López-Sanchez, Francisco Gracia-Navarro & Raul M Luque

Instituto Maimomnides de Investigacion Biomedica de Cordoba (IMIBIC)-University of Cordoba-HURS, Cordoba, Spain.

Somatostatin receptors (sst1–sst5) comprise a family of G-protein-coupled, 7 transmembrane domain (TMD) receptors encoded by five separate, intronless genes widely distributed throughout the organism. Somatostatin (SST) and cortistatin (CORT), two highly-related cyclic neuropeptides, bind to sst1–sst5 with comparable subnanomolar affinity to exert a number of (patho)physiological actions, from inhibition of endocrine secretions (e.g. GH and insulin), to the control of metabolic homeostasis, neurotransmission, or gastrointestinal and immune function. In addition, SST can also act via sst to inhibit tumour cell growth. Hence, SST analogues are used to treat endocrine/tumour pathologies. This notwithstanding, there was evidence that not all SST/CORT actions could be explained by their interaction with the five known sst. In this scenario, our group has recently identified novel truncated variants of sst5 in human, pig, mouse, and rat, which lack one or more TMD and exhibit unique molecular and functional features. Thus, each truncated sst5 variant displays a distinct tissue distribution in every species examined, and exhibits disparate, selective responses to SST and CORT when expressed on heterologous cell lines. In general, truncated sst5 variants show a preferential intracellular distribution that contrasts with the typical plasma-membrane localization of full-length ssts. Moreover, in cells coexpressing truncated sst5 variants and full-length sst5 or sst2, we observe that truncated and full-length receptors colocalize and physically interact, such interaction likely providing the molecular basis for truncated sst5 variants to disrupt the normal response of sst2/sst5 to SST and CORT. In humans, sst5TMD4 expression was found to be very rare and scarce in normal tissues. However, this receptor was frequently and abundantly expressed in pituitary tumours, particularly in somatotropinomas, where its presence was inversely correlated with GH reduction by SST analogues both in vivo and in vitro. Furthermore, sst5TMD4 is present in a subset of breast tumours, where it is associated to bad prognosis markers, and increases malignancy features of MCF-7 breast cancer cells by acting as a dominant negative for SST action. Study of these new truncated sst5 variants paves the way to explore novel aspects of sst pathophysiology and to expand their therapeutic potential.

Funding: BFU2010-19300, BFU2008-01136/BFI, RYC-2007-00186, CTS-5051 BIO-139.

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