Selective stimulation of somatostatin receptor subtypes: differential effects on Ras/MAP kinase pathway and cell proliferation in human neuroblastoma cells

Abstract

In previous studies we have showed that somatostatin (SST) inhibits cell division, mitogen-activated protein (MAP) kinase and Ras activity in the human neuroblastoma cell line SY5Y. In the present study, we have assessed the role of a series of SST analogs, three of which were selective for SSTR1, SSTR2 or SSTR5, in these cellular events. All the analogs inhibited forskolin-induced cAMP accumulation. Selective stimulation of SSTR1 or SSTR2 but not of SSTR5 inhibited platelet-derived growth factor (PDGF)-induced [ 3 H]thymidine incorporation. The three analogs inhibited PDGF-stimulated MAP kinase activity, at least at an early time. In contrast, none of the analogs used individually was able to inhibit PDGFstimulated Ras activity. A combined stimulation of SSTR2 and SSTR5 was necessary to obtain a significant inhibitory effect, suggesting the possibility of receptor heterodimerization. These results indicate that SST inhibition of Ras and MAP kinase activities takes place via different pathways and that SST inhibition of PDGF-induced cell proliferation occurs via a Rasindependent pathway. ß

Anti-migratory and Anti-invasive Effect of Somatostatin in Human Neuroblastoma Cells

“…It has been suggested that somatostatin receptor (SSTR) expression is a favorable prognostic factor in human neuroblastoma because high levels of SSTR type 2 positively relate to patient survival (9,10). In previous studies, we have shown that somatostatin inhibits proliferation, ERK 1/2 and Ras activity in SH-SY5Y cells (11,12), and that these cells express all five SSTR subtypes (13). Moreover, it has also been reported that somatostatin can inhibit human endothelial-like EAhy926 cell invasion and monocyte migration (14), and these effects have been related to its ability to impair the angiogenic process.…”

“…To verify whether somatostatin possesses anti-migratory and anti-invasive properties, we studied its effects on PDGF-induced motility and invasion in SH-SY5Y cells, previously characterized in our laboratory for the expression of multiple SSTR subtypes (13). Pretreatment of the cells with somatostatin inhibited the migration and invasion induced by PDGF 20 ng/ml in a concentration-dependent manner (Fig.…”

Overexpression of SSTR2 inhibited the growth of SSTR2-positive tumors via multiple signaling pathways

“…The two peptides produced by SST cells act as neurotransmitters or paracrine/ autocrine regulators via five different subtypes of human SSTRs (SSTR1-5), encoded by five distinct SSTR genes segregated on chromosome 14,16,17,20,22 [1]. The highest homology of hSSTRs have been found in their transmembrane domains (TM), with a highly conserved sequence, YANSCANPI/ VLY, in the seventh TM, found in all human SSTRs as well as in other species [2].…”

“…Nonetheless, the detailed mechanisms of the SSTRmediated inhibition of tumor growth remain to be further investigated. Also, intracellular pathways involved in SSTR signaling may need to be studied in each individual case since subtype-and cell typespecific signaling components have been reported [1,14]. However, despite of the contradictory information obtained in different cell types using different SST analogues, it is generally accepted that all five SSTR subtypes are coupled to inhibition of the adenylyl cyclase-cAMP pathway and stimulate phosphotyrosyl protein phosphatase (PTP) [2].…”

“…However, despite of the contradictory information obtained in different cell types using different SST analogues, it is generally accepted that all five SSTR subtypes are coupled to inhibition of the adenylyl cyclase-cAMP pathway and stimulate phosphotyrosyl protein phosphatase (PTP) [2]. All five subtypes also interfere with the MAPK pathway to modulate cell proliferation, although the precise mechanisms seem to be subtype-and cell typespecific [14,15].…”