ECE2016 Oral Communications Endocrine Tumours (5 abstracts)
The truncated somatostatin receptor sst5TMD4 is overexpressed in prostate cancer, where it increases aggressiveness features by regulating key tumor suppressors and oncogenes.
Daniel Hormaechea-Agulla 1 , Juan Manuel Jiménez-Vacas 1 , Alejandro Ibañez-Costa 1 , Enrique Gómez-Gómez 2 , Julia Carrasco-Valiente 2 , José Valero Rosa 2 , María M Moreno 3 , Michael D Culler 4 , Manuel D Gahete 1 , María José Requena 2 , Justo P Castaño 1 & Raúl M Luque 1
1Department of Cell Biology, Physiology and Immunology, University of Córdoba, Hospital Universitario Reina Sofía (HURS), Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), CIBERobn, Córdoba, Spain; 2Urology Service, HURS/IMIBIC., Córdoba, Spain; 3Anatomopathology Service, HURS/IMIBIC, Córdoba, Spain; 4IPSEN Bioscience, Cambridge, MA, USA.
Somatostatin is a pleiotropic neuropeptide that governs multiple biological targets, including tumor cell function, through a family of G protein-coupled receptors with 7-transmembrane domains (TMD), named sst1-5. However, we recently discovered sst5TMD4, an aberrantly spliced, truncated (only 4-TMDs) sst5-variant displaying unique molecular/functional features. sst5TM4 is overexpressed in various endocrine-related tumors exacerbating their malignant characteristics. Here, we present the first analysis of the presence, pathological relevance, functional role, and mechanisms of action of sst5TMD4 in human prostate cancer (PCa). Specifically, samples from human PCa, normal prostate (NP), and PCa cell lines (VCaP and PC3) were studied. Expression profiles were determined by qPCR and functional consequences of sst5TMD4 overexpression/inhibition were analyzed using different techniques. Intracellular mechanisms triggered by sst5TMD4 overexpression were determined using commercial arrays. Preclinical mouse models were used to study the in vivo consequences of sst5TMD4 overexpression on tumor growth. Our results revealed that sst5TMD4 was overexpressed in PCa samples, and its expression was higher in patients with metastatic PCa. In PCa cell lines, sst5TMD4 overexpression increased cell proliferation and migration, while its silencing reduced cell proliferation. sst5TMD4 overexpression stimulated key intracellular pathways involved in PCa function, including ERK/JNK, MYC/MAX, WNT and RB, and, consequently, altered the expression of tumor suppressors (APC, SFRP1, CDKN2A, ZNF185) and oncogenes (CAV1, IL-6, DAXX). Notably, sst5TMD4-transfected PC3 cells lost their usual response to somatostatin analogs in terms of calcium kinetics, evidencing the disruption of normal functioning of somatostatin system in PCa. Finally, nude mice injected with sst5TMD4 stably-transfected PC3 cells presented larger tumors with increased proportion of necrosis. In conclusion, sst5TMD4 is overexpressed in PCa, where it is associated to the presence of metastasis, and promotes aggressiveness features in in vitro and in vivo models, suggesting its potential value as biomarker and/or therapeutic target in PCa.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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