Regulation of prostate cancer cell proliferation by somatostatin receptor activation

Abstract

Although some evidence supports the antitumoral effects of somatostatin (SRIF) and related agonists, the available data in prostate cancer (PCa) model systems and clinical studies are few, conflicting and not conclusive. This study investigated the effects of lanreotide and new mono-and bi-specific SRIF agonists on proliferation, ligand-driven SRIF receptor (sst) dimerization and secretory pattern of the IGF system in LNCaP cells, a model of androgendependent PCa. LNCaP expressed all sst s , but sst 4. Among them, sst 1 and sst 3 were inversely regulated by serum concentration. Sst 1 /sst 2 and sst 2 /sst 5 dimers were constitutively present and further stabilized by treatment with BIM-23704 (sst 1 /sst 2) and BIM-23244 (sst 2 /sst 5), respectively. Dose-response studies showed that lanreotide and BIM-23244 were significantly more potent in inhibiting LNCaP cell proliferation than BIM-23120 (sst 2) and BIM-23206 (sst 5) alone or in combination. Treatment with BIM-23296 (sst 1) markedly reduced cell proliferation, whereas exposure to BIM-23704 resulted in a lower cell growth inhibition. The antiproliferative effects of BIM-23244, lanreotide and BIM-23704 were unchanged, reduced and abolished by the sst 2 antagonist BIM-23627, respectively. All SRIF analogs caused a significant induction in p27 KipI and p21 and down-regulation of protein expression of cyclin E, as well as reduced IGF-I and IGF-II secretion. In particular, the administration of exogenous IGF-I, at variance to IGF-II, counteracted the inhibitory effect on cell proliferation of these compounds. Moreover, SRIF agonists reduced endogenous IGFBP-3 proteolysis. These results show that, in LNCaP cells, activation of sst 1 and sst 2 /sst 5 results in relevant antiproliferative/antisecretive actions. INTRODUCTION Somatostatin (SRIF) is an inhibitory tetradecapeptide hormone with exocrine, endocrine, paracrine, and autocrine activities, which plays an important regulatory role in several cell functions, including inhibition of endocrine secretion and cell proliferation (Hejna et al., 2002; Tejeda et al., 2006). Most of the effects of SRIF and of its currently available analogs are mediated via five different G protein-coupled receptor (GPCRs), codenamed sst 1-5 (Patel 1999). Sst s are expressed in a tissue-and subtype-selective manner in both normal and neoplastic cells, and the majority of SRIF target tissues express multiple sst s (Reubi et al., 2001). Recent data suggest that when sst s are coexpressed may interact forming homo-and hetero-dimers also with other GPCRs, altering their original pharmacological and functional profiles (Krantic et al., 2004). Prostate cancer (PCa) is the most frequently diagnosed malignant neoplasm among men in the Western world and remains the second leading cause of cancer-related deaths, with an incidence estimated at 12% in the European Union and at 29% in the USA (Djavan 2007). In addition to the traditional anti-androgen hormonal therapy, commonly used in androgendependent PCa, some evidence suggest SRIF receptors as a ta...

Somatostatin and dopamine receptor interaction in prostate and lung cancer cell lines

“…LNCaP cell line D 2 R gene and protein expression We have already reported the SSTR and D 2 R profile in Calu-6, as well as the SSTR content in LNCaP (Ferone et al 2005, Ruscica et al 2010, hence, before any test we sought to determine the gene and protein expression of D 2 R in LNCaP cells, by means of RT-PCR and western blot analysis. By using specific oligoprimers, we detected a product of 523 bp corresponding to the D 2 R mRNA.…”

“…Moreover, almost all studies carried out on cell lines showed receptor dimerization in transfected models highly expressing at least two receptor subtypes (Rocheville et al 2000a, Pfeiffer et al 2001, Ren et al 2003. In this study, we have used two tumor cell lines constitutively expressing four (LNCaP) and three (Calu-6) out of the five SRIF receptors (Ferone et al 2005, Ruscica et al 2010) and the D 2 R. These non-neuroendocrine cell lines, because of their constitutive and relatively low receptor expression, represent a useful model to investigate the physiological mechanisms involved in protein membrane interaction, such as receptor dimerization. Since recently new SRIF analogues with a specific affinity for given receptor subtypes, and SRIF/DA chimeric compounds have been developed (Ferone et al 2005, Saveanu & Jaquet 2009, in this study we have investigated the effect of these compounds on receptor interaction, and correlated the occurrence of co-immunoprecipitated receptors with the impact on cell proliferation.…”

“…Since we already demonstrated a dose-response effect of these compounds in the inhibition of cell proliferation (Ferone et al 2005), in this study, we have performed all experiments using the concentration of compounds that demonstrated about a 50% inhibitory effect (10 K9 M). According to the baseline expression of SSTR subtypes in the two cell lines (Ferone et al 2005, Ruscica et al 2010 and to the ineffectiveness of a 24 h treatment on receptor expression, we tested specific SRIF analogues in order to study the different combinations of (potential) receptor interaction. Indeed, in LNCaP cell line, we tested the bi-specific SRIF compounds targeting sstr 1 , sstr 2 , and sstr 5 , and in Calu-6 cell line, the bi-specific SRIF compounds targeting sstr 2 and sstr 5 .…”

“…In this study, we analyzed the effects of different SRIF analogues and of one SRIF/DA chimeric compound on SSTRs and D 2 R interaction on cell membrane and cell proliferation in a cell line constitutively expressing four out of five SSTRs, the androgen-dependent prostate cancer cell line LNCaP (Ruscica et al 2010), and in a cell line constitutively expressing three out of four SSTRs and the D 2 R, the non-small cell lung cancer (NSCLC) line Calu-6 (Ferone et al 2005).…”

Somatostatin Receptors 3, 4 and 5 Play Important Roles in Gallbladder Cancer

“…SSTR 1, SSTR2, SSTR 4, and SSTR 5 are concerned with the blockade of cell cycle and could block cell in G1/G0periond (Buscail et al, 2002;Bousquet et al, 2004). SST can adjust apoptosis via SSTR2 and SSTR3 (Ruscica et al, 2010). …”