A growing number of studies suggest that extracellular fragments derived from plasma membrane receptors can play relevant functional roles in the development and progression of certain tumoral pathologies which might, therefore, serve as novel tools in the diagnostic and prognostic of such pathologies. In this scenario, the truncated somatostatin receptor sst5TMD4, which is overexpressed in various endocrine-related cancers (i.e. breast, prostate, neuroendocrine, liver and pituitary), is an aberrant splicing variant with only 4 transmembrane domains, wherein its C-terminal tail is exposed towards the extracellular matrix and could, therefore, be the substrate for proteolytic enzymes. Thus, to explore the plausible generation of soluble peptides derived from the sst5TMD4 extracellular domain and their potential patho-physiological implications, in silico and in vitro approaches were implemented using several cancer-derived cell lines (i.e. breast, prostate, neuroendocrine and liver). Firstly, in silico analysis predicted the existence of two cleavage sites for metalloproteases (MMP) 2, 9, 14 and/or 16, which could generate the release of three possibly soluble peptides. We, then, chemically synthetized these sst5TMD4-derived peptides and demonstrated that they were able to enhance malignancy features (proliferation, migration and dedifferentiation processes) in all the tumoral cell lines tested, probably acting through PI3K/Akt and/or MEK/ERK signalling pathways. Moreover, treatment with sst5TMD4-derived peptides altered the expression pattern of several genes involved in cancer development and progression (e.g. certain MMPs, Ki67, ARP2/3 or CD24/44). Therefore, based on these results, it is possible that sst5TMD4-derived peptides could be linked to the pathological role of sst5TMD4 previously observed in these tumoral pathologies. Altogether, these studies provide new information about the patho-physiological role of this truncated variant of sst5 and suggest that sst5TMD4-derived peptides could be potential candidates for future studies aimed to identify novel diagnostic, prognostic and/or therapeutic targets in certain endocrine-related cancers.
20 - 23 May 2017
European Society of Endocrinology