Characterization and sub-cellular localization of SS1R,SS2R,and SS5R in human late-stage prostate cancer cells: Effect of mono- and bi-specific somatostatin analogs on cell growth |
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Authors: | M. Ruscica P. Magni L. Steffani F. Gatto M. Albertelli R. Rametta L. Valenti P. Ameri V. Magnaghi M.D. Culler F. Minuto D. Ferone M. Arvigo |
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Affiliation: | 1. Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy;2. Department of Internal Medicine and Medical Specialities & Center of Excellence for Biomedical Research, IRCCS AOU San Martino-IST, Università di Genova, Italy;3. Pathophysiology and Transplantation, Università degli Studi di Milano, UO Medicina Interna 1B, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Italy;4. Biomeasure Incorporated/IPSEN, Milford, MA, USA |
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Abstract: | Somatostatin (SST) and SST receptors (SS1R, SS2R, SS3R, SS4R and SS5R) appear to play a significant role in the progression of human prostate cancer (PCa), which is associated with heterogeneity of SSRs expression and specific cell localization as we already demonstrated in the LNCaP cell line, an in vitro model of human androgen-dependent PCa. In this study, PC-3 and DU-145 human castration-resistant PCa cells were found to express all SSRs, while LNCaP expressed all but SS4R. A 48-h treatment with BIM-23244 (SS2R/SS5R) or BIM-23926 (SS1R) SST analogs was more effective in inhibiting cell proliferation, compared to BIM-23120 (SS2R), BIM-23206 (SS5R) and BIM-23704 (SS1R/SS2R). BIM-23926 (SS1R) treatment increased the amount of p21 and decreased phosphorylated (p) ERK1/2. BIM-23244 (SS2R/SS5R) led to p21 increment only in PC-3 cells, and to pERK1/2 reduction in both cell lines. SS1R/SS2R and SS2R/SS5R receptor dimers were natively present on cell membrane and their amount was increased by BIM-23704 (SS1R/SS2R) or BIM-23244 (SS2R/SS5R) treatment, respectively. SS1R, SS2R and SS5R were differently distributed among nuclear, lysosomal and microsomal compartment, according to their different recycling dynamics. These results show that, in PC-3, DU-145 and LNCaP cells, activation of SS1R and SS2R/SS5R leads to relevant antiproliferative effects. |
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Keywords: | SST, somatostatin SSTR, human somatostatin receptor (mRNA) SSR, human somatostatin receptor (protein) SSAs, somatostatin analogs PCa, prostate cancer ATP, adenosine triphosphate FAM, fluorescent dye 6-carboxy-fluorescein CDS, coding sequences BrdU, 5&prime -bromo-2&prime deoxyuridine PDI, protein disulfide isomerase P, phosphorylated MAPK, mitogen-activated protein kinase IGF, insulin-like growth factor CTR, control |
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