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Submitted on July 9, 2004
Accepted on September 14, 2004
Sect. Pharmacology, Dept. Oncology, Biology and Genetics University of Genova and, Pharmacology and Neuroscience, National Institute for Cancer Research (IST) Genova
* To whom correspondence should be addressed. E-mail: florio{at}cba.unige.it.
We previously reported that, beside 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 NO production induced by different agonists (bFGF, insulin, CCK) and the intracellular signaling involved, using CHO-k1 cells stably transfected with individual SST receptor 1-4. bFGF and insulin induced eNOS activity via the generation of ceramide or the Akt-dependent phosphorylation of eNOS, respectively. CCK regulates nNOS activity in a Ca++-dependent manner. SST inhibited NO production stimulated by bFGF through SSTR1,2 and 3 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 down-stream the receptor phosphorylation and ceramide synthesis. SSTR2 and 3 on CCK activity were related to the inhibition of intracellular Ca++ mobilization, while 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 perspective in the use of SST agonists to control tumoral angiogenesis.
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