Endocrine Abstracts

Somatostatin (SST) and its related peptide cortistatin (CORT) exert multiple physiological actions through binding to a family of G-protein coupled receptors (sst1–sst5), commonly bearing seven transmembrane domains (TMDs). However, we have recently discovered that human, pig and rodent sst5 gene also generate, through non-canonical alternative splicing, novel truncated albeit functional sst5 variants that lack one o more TMDs. Our studies indicate that truncated sst5 variants are key elements of the sst family with unique molecular features and functional capacities in mammals, where they can directly interact with long, 7TMD variants (i.e. sst2) and modulate the normal and pathological cellular response to SST/CORT in terms of signaling pathways, hormone secretion and proliferation. Specifically, we have observed that human truncated sst5TMD4 is absent in normal pituitaries and mammary gland tissues but is present in pituitary and breast tumors, in association with long sst5 and/or sst2. In fact, our results indicate that sst5TMD4 might play a relevant patho-physiological role, probably by modulating/impairing the actions of long ssts, which are commonly used as pharmacological targets to treat endocrine/tumoral pathologies (octreotide/lanreotide). Indeed, when coexpressed in the same cell, truncated sst5TMD4 colocalizes and physically interacts with long ssts, providing a molecular basis for the ability of sst5TMD4 to disrupt the normal functioning of sst2/sst5. Moreover, our results indicate that sst5TMD4 is selectively expressed in the most aggressive cases of breast and pituitary tumors, as shown by its correlation with prognostic/proliferative markers. Most importantly, the presence of sst5TMD4 increased malignancy features (i.e. enhanced invasion and/or proliferation abilities) in breast cancer and pituitary tumor cells. Altogether, these results suggest that sst5TMD4 could be involved in the pathophysiology of certain types of tumours, which offer novel avenues to identify and develop original molecular targets for the future diagnosis, prognostic and/or therapeutic treatment of these human pathologies.

Declaration of funding: BFU2010-19300, BIO-0139, CTS-5051, PI-0639-2012, CIBERobn.