Somatostatin receptor subtype-dependent regulation of nitric oxide release: involvement of different intracellular pathways.
We reported previously that, in addition to direct effects, somatostatin (SST) affects tumor growth inhibiting the tumoral neoangiogenesis, via an interference with NO synthesis. Here, we analyzed the effects of SST on nitric oxide (NO) production induced by different agonists [basic fibroblast growth factor (bFGF), insulin, cholecystokinin (CCK)] and the intracellular signaling involved, using Chinese hamster ovary-k1 cells stably transfected with individual SSTR1-SSTR4. bFGF and insulin induced endothelial nitric oxide synthase activity via the generation of ceramide or the Akt-dependent phosphorylation of endothelial nitric oxide synthase, respectively. CCK regulates neuronal nitric oxide synthase activity in a Ca++-dependent manner. SST inhibited NO production stimulated by bFGF through SST receptor 1 (SSTR1), SSTR2, and SSTR3 and by CCK through SSTR2 and SSTR3. In all the cell lines, SST treatment did not modify NO synthesis induced by insulin. SSTR4 activation was not effective on any of the stimuli tested. The effects on bFGF-induced NO production were downstream from receptor phosphorylation and ceramide synthesis. SSTR2 and -3 on CCK activity were related to the inhibition of intracellular Ca++ mobilization, whereas the lack of effects on insulin was paralleled by the absence of SST activity on Akt phosphorylation. These data, identifying for the first time a selective receptor subtype-inhibitory role of SST on NO generation, may open new perspectives in the use of SST agonists to control tumoral angiogenesis.
Arena
Sara
S
Section of Pharacology, Department of Oncology, Biology and Genetics, University of Genova, and Pharmacology and Neuroscience, National Institute for Cancer Research (IST), 16132 Genova, Italy.
Pattarozzi
Alessandra
A
Corsaro
Alessandro
A
Schettini
Gennaro
G
Florio
Tullio
T
D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002518:Ceramides / Q000494:pharmacology; D002766:Cholecystokinin / Q000494:pharmacology; D006224:Cricetinae; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; D010766:Phosphorylation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017481:Receptors, Somatostatin / Q000145:classification* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013004:Somatostatin / Q000494:pharmacology
D002518:Ceramides; D007328:Insulin; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D017481:Receptors, Somatostatin; D016222:Fibroblast Growth Factor 2; D009569:Nitric Oxide; D013004:Somatostatin; D002766:Cholecystokinin; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; C496322:Nos1 protein, rat; C496316:Nos3 protein, rat; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D002118:Calcium