Sergio Pedraza-Arévalo1,2,3,4, Daniel Hormaechea-Agulla1,2,3,4, Enrique Gómez-Gómez1,2,3,5, María J Requena1,2,3,5, Luke A Selth6, Manuel D Gahete1,2,3,4, Justo P Castaño1,2,3,4, Raul M Luque1,2,3,4. 1. Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain. 2. Department of Cell Biology, Physiology, and Immunology, Universidad de Córdoba, Córdoba, Spain. 3. Reina Sofia University Hospital, Córdoba, Spain. 4. CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain. 5. Urology Service, Reina Sofia University Hospital, Córdoba, Spain. 6. Dame Roma Mitchell Cancer Research Laboratories and Freemasons Foundation Centre for Men's Health, Adelaide Medical School, The University of Adelaide, SA, 5005, Australia.
Abstract
BACKGROUND: Prostate cancer (PCa) is a highly prevalent neoplasia that is strongly influenced by the endocrine system. Somatostatin (SST) and its five receptors (sst1-5 encoded by SSTR1-5 genes) comprise a pleiotropic system present in most endocrine-related cancers, some of which are successfully treated with SST analogs. Interestingly, it has been reported that SSTR1 is overexpressed in PCa, but its regulation, functional role, and clinical implications are still poorly known. METHODS: PCa specimens (n = 52) from biopsies and control prostates from cystoprostatectomies (n = 12), as well as in silico databases were used to evaluate SSTR1 and miRNAs expression. In vitro studies in 22Rv1 PCa cells were implemented to explore the regulation of SSTR1/sst1 by different miRNAs, and to evaluate the consequences of SSTR1/sst1 overexpression, silencing and/or activation [with the specific BIM-23926 sst1 agonist (IPSEN)] on cell-proliferation, migration, signaling-pathways, and androgen-signaling. RESULTS: We found that SSTR1 is overexpressed in multiple cohorts of PCa samples, as compared with normal prostate tissues, wherein it correlates with androgen receptor (AR) expression, and appears to be associated with aggressiveness (metastasis). Furthermore, our data revealed that SSTR1/sst1 expression might be regulated by specific miRNAs in PCa, including miR-24, which is downregulated in PCa samples and correlates inversely with SSTR1 expression. In vitro studies indicated that treatment with the BIM-23926 sst1 agonist, as well as SSTR1 overexpression, decreased, whereas SSTR1 silencing increased, cell-proliferation in 22Rv1 cells, likely through the regulation of PI3K/AKT-CCND3 signaling-pathway. Importantly, sst1 action was also able to modulate androgen/AR activity, and reduced PSA secretion from PCa cell lines. CONCLUSIONS: Altogether, our results indicate that SSTR1 is overexpressed in PCa, where it can exert a relevant pathophysiological role by decreasing cell-proliferation and PSA secretion. Therefore, sst1, possibly in combination with miR-24, could be used as a novel tool to explore therapeutic targets in PCa.
BACKGROUND:Prostate cancer (PCa) is a highly prevalent neoplasia that is strongly influenced by the endocrine system. Somatostatin (SST) and its five receptors (sst1-5 encoded by SSTR1-5 genes) comprise a pleiotropic system present in most endocrine-related cancers, some of which are successfully treated with SST analogs. Interestingly, it has been reported that SSTR1 is overexpressed in PCa, but its regulation, functional role, and clinical implications are still poorly known. METHODS: PCa specimens (n = 52) from biopsies and control prostates from cystoprostatectomies (n = 12), as well as in silico databases were used to evaluate SSTR1 and miRNAs expression. In vitro studies in 22Rv1 PCa cells were implemented to explore the regulation of SSTR1/sst1 by different miRNAs, and to evaluate the consequences of SSTR1/sst1 overexpression, silencing and/or activation [with the specific BIM-23926 sst1 agonist (IPSEN)] on cell-proliferation, migration, signaling-pathways, and androgen-signaling. RESULTS: We found that SSTR1 is overexpressed in multiple cohorts of PCa samples, as compared with normal prostate tissues, wherein it correlates with androgen receptor (AR) expression, and appears to be associated with aggressiveness (metastasis). Furthermore, our data revealed that SSTR1/sst1 expression might be regulated by specific miRNAs in PCa, including miR-24, which is downregulated in PCa samples and correlates inversely with SSTR1 expression. In vitro studies indicated that treatment with the BIM-23926 sst1 agonist, as well as SSTR1 overexpression, decreased, whereas SSTR1 silencing increased, cell-proliferation in 22Rv1 cells, likely through the regulation of PI3K/AKT-CCND3 signaling-pathway. Importantly, sst1 action was also able to modulate androgen/AR activity, and reduced PSA secretion from PCa cell lines. CONCLUSIONS: Altogether, our results indicate that SSTR1 is overexpressed in PCa, where it can exert a relevant pathophysiological role by decreasing cell-proliferation and PSA secretion. Therefore, sst1, possibly in combination with miR-24, could be used as a novel tool to explore therapeutic targets in PCa.
Authors: Sara L Jepsen; Kaare V Grunddal; Nicolai J Wewer Albrechtsen; Maja S Engelstoft; Maria B N Gabe; Elisa P Jensen; Cathrine Ørskov; Steen S Poulsen; Mette M Rosenkilde; Jens Pedersen; Fiona M Gribble; Frank Reimann; Carolyn F Deacon; Thue W Schwartz; Andreas D Christ; Rainer E Martin; Jens J Holst Journal: Am J Physiol Endocrinol Metab Date: 2019-09-10 Impact factor: 4.310
Authors: Enrique Gómez-Gómez; Juan M. Jiménez-Vacas; Sergio Pedraza-Arévalo; Fernando López-López; Vicente Herrero-Aguayo; Daniel Hormaechea-Agulla; José Valero-Rosa; Alejandro Ibáñez-Costa; Antonio J. León-González; Rafael Sánchez-Sánchez; Teresa González-Serrano; Maria J. Requena-Tapia; Justo P. Castaño; Julia Carrasco-Valiente; Manuel D. Gahete; Raúl M. Luque Journal: J Clin Med Date: 2019-09-06 Impact factor: 4.241
Authors: Run Shi; Xuanwen Bao; Joachim Weischenfeldt; Christian Schaefer; Paul Rogowski; Nina-Sophie Schmidt-Hegemann; Kristian Unger; Kirsten Lauber; Xuanbin Wang; Alexander Buchner; Christian Stief; Thorsten Schlomm; Claus Belka; Minglun Li Journal: Cancers (Basel) Date: 2019-12-18 Impact factor: 6.639
Authors: Juan M Jiménez-Vacas; Vicente Herrero-Aguayo; Antonio J Montero-Hidalgo; Enrique Gómez-Gómez; Antonio C Fuentes-Fayos; Antonio J León-González; Prudencio Sáez-Martínez; Emilia Alors-Pérez; Sergio Pedraza-Arévalo; Teresa González-Serrano; Oscar Reyes; Ana Martínez-López; Rafael Sánchez-Sánchez; Sebastián Ventura; Elena M Yubero-Serrano; María J Requena-Tapia; Justo P Castaño; Manuel D Gahete; Raúl M Luque Journal: EBioMedicine Date: 2020-01-03 Impact factor: 8.143