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 androgen-dependent 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-23926 [corrected] (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.

• Authors: Massimiliano Ruscica, Marica Arvigo, Federico Gatto, Elena Dozio, Daniel Feltrin, Michael D Culler, Francesco Minuto, Marcella Motta, Diego Ferone, Paolo Magni
• Journal: Molecular and cellular endocrinology (Mol Cell Endocrinol) Vol. 315 Issue 1-2 Pg. 254-62 (Feb 05 2010) ISSN: 1872-8057 [Electronic] Ireland
• PMID: 19932151 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: 2009 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• BIM 23120
• BIM 23206
• BIM-23244
• Culture Media, Conditioned
• Peptides, Cyclic
• Receptors, Somatostatin
• lanreotide
• Somatostatin
• Insulin-Like Growth Factor I
• Insulin-Like Growth Factor II

Topics

• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor (drug effects)
• Cell Proliferation (drug effects)
• Culture Media, Conditioned (chemistry, metabolism)
• Dose-Response Relationship, Drug
• Humans
• Insulin-Like Growth Factor I (metabolism)
• Insulin-Like Growth Factor II (metabolism)
• Male
• Peptides, Cyclic (pharmacology)
• Prostatic Neoplasms (metabolism, pathology)
• Receptors, Somatostatin (genetics, metabolism)
• Somatostatin (analogs & derivatives, metabolism, pharmacology)