Characterization and sub-cellular localization of somatostatin receptors in DU-145 and PC-3 human androgen-independent prostate cancer cells: effect of mono- and bi-specific somatostatin analogs on cell growth

Somatostatin (SRIF) is an inhibitory hormone that plays a regulatory role in several cell functions including cell proliferation. SRIF acts through five specific membrane receptors (sst1-5), expressed on SRIF-target cells. SRIF and ssts may play a significant role in the progression and neuroendocrine differentiation of human prostate cancer (PCa). However, conflicting results have been reported in the literature on ssts heterogeneity and specific cell localization in PCa. Aim of this study was to evaluate in two androgen-independent human PCa cell lines DU-145 and PC-3 cells: (a) the gene and protein expression of ssts; (b) the sub-cellular localization of the different ssts; (c) the effects of new mono- and bispecific SRIF analogs (SSAs) on cell proliferation and activation of proteins involved in the regulation of the cell cycle; (d) the constitutive and SSAs-driven ssts dimerization. DU-145 and PC-3 cells express all SRIF receptors at both gene (SSTR1-5) and protein (sst1-5) levels. Moreover, sst1/sst2 and sst2/sst5 receptor dimers were constitutively present at the cell membrane. A 48 h treatment with BIM-23704 (sst1/sst2) and BIM-23244 (sst2/ss5) compounds increased the amount of sst1/sst2 and sst2/sst5 dimers, respectively. Sub-cellular organelle separation of cell lysates showed a different sst1, sst2 and sst5 nuclear, lysosomal and microsomal distribution, according to the different recycling dynamics of these isoforms. In DU-145 and PC-3 cells, a 48 h treatment with BIM-23244 (sst2/5) and BIM-23926 (sst1) analogs were more effective in inhibiting cell proliferation (−30%) in the dose-range tested (10−10–10−6 M), compared to BIM-23120 (sst2), BIM-23206 (sst5) and BIM-23704 (sst1/sst2) compounds. Moreover, in DU-145 cells BIM-23244 and BIM-23926 activated p21 and phosphorylated ERK, two proteins involved in cell cycle arrest. In conclusion, DU-145 and PC-3 cells represent a useful PCa model for studying ssts trafficking/regulation, intracellular subtype-linked signaling, and validating new sst-specific SRIF analogs aimed at PCa treatment.