TY - JOUR
T1 - Regulation of prostate cancer cell proliferation by somatostatin receptor activation
AU - Ruscica, Massimiliano
AU - Arvigo, Marica
AU - Gatto, Federico
AU - Dozio, Elena
AU - Feltrin, Daniel
AU - Culler, Michael D.
AU - Minuto, Francesco
AU - Motta, Marcella
AU - Ferone, Diego
AU - Magni, Paolo
PY - 2010/2/5
Y1 - 2010/2/5
N2 - 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 ssts, but sst4. Among them, sst1 and sst3 were inversely regulated by serum concentration. sst1/sst2 and sst2/sst5 dimers were constitutively present and further stabilized by treatment with BIM-23704 (sst1/sst2) and BIM-23244 (sst2/sst5), respectively. Dose-response studies showed that lanreotide and BIM-23244 were significantly more potent in inhibiting LNCaP cell proliferation than BIM-23120 (sst2) and BIM-23206 (sst5) alone or in combination. Treatment with BIM-23296 (sst1) 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 sst2 antagonist BIM-23627, respectively. All SRIF analogs caused a significant induction in p27KipI 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 sst1 and sst2/sst5 results in relevant antiproliferative/antisecretive actions.
AB - 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 ssts, but sst4. Among them, sst1 and sst3 were inversely regulated by serum concentration. sst1/sst2 and sst2/sst5 dimers were constitutively present and further stabilized by treatment with BIM-23704 (sst1/sst2) and BIM-23244 (sst2/sst5), respectively. Dose-response studies showed that lanreotide and BIM-23244 were significantly more potent in inhibiting LNCaP cell proliferation than BIM-23120 (sst2) and BIM-23206 (sst5) alone or in combination. Treatment with BIM-23296 (sst1) 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 sst2 antagonist BIM-23627, respectively. All SRIF analogs caused a significant induction in p27KipI 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 sst1 and sst2/sst5 results in relevant antiproliferative/antisecretive actions.
KW - Androgen-dependent prostate cancer
KW - Cell proliferation
KW - IGFs system
KW - Somatostatin analogs
KW - Somatostatin receptor subtypes dimerization
UR - http://www.scopus.com/inward/record.url?scp=71849088362&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=71849088362&partnerID=8YFLogxK
U2 - 10.1016/j.mce.2009.11.006
DO - 10.1016/j.mce.2009.11.006
M3 - Article
C2 - 19932151
AN - SCOPUS:71849088362
VL - 315
SP - 254
EP - 262
JO - Molecular and Cellular Endocrinology
JF - Molecular and Cellular Endocrinology
SN - 0303-7207
IS - 1-2
ER -