Selective stimulation of somatostatin receptor subtypes: differential effects on Ras/MAP kinase pathway and cell proliferation in human neuroblastoma cells.
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 PDGF-stimulated 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 Ras-independent pathway.
Cattaneo
M G
MG
Department of Pharmacology, University of Milano, Via Vanvitell 32, 20129 Milan, Italy.
Taylor
J E
JE
Culler
M D
MD
Nisoli
E
E
Vicentini
L M
LM
D000818:Animals; D016466:CHO Cells; D002455:Cell Division / Q000502:physiology; D006224:Cricetinae; D000242:Cyclic AMP / Q000096:biosynthesis; D004789:Enzyme Activation; D006133:Growth Substances / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D009447:Neuroblastoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D017481:Receptors, Somatostatin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology
D006133:Growth Substances; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D017481:Receptors, Somatostatin; C103631:somatostatin receptor 3; C101130:somatostatin receptor type 1; C094573:somatostatin receptor 5; C093733:somatostatin receptor 2; D000242:Cyclic AMP; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins