Somatostatin receptor subtype-dependent regulation of nitric oxide release: Involvement of different intracellular pathways
Somatostatin receptor subtype-dependent regulation of nitric oxide release: Involvement of different intracellular pathways
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DOI：
10.1210/me.2004-0280
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发表时间：
2005-01-01
影响因子：
--
通讯作者：
Florio, T
中科院分区：
文献类型：
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作者：
Arena, S;Pattarozzi, A;Florio, T
我们以前报道过，除了直接作用外，生长抑素（SST）通过干扰NO的合成来影响肿瘤生长，抑制肿瘤新生血管的生成。在这里，我们分析了SST对不同的激动剂[碱性成纤维细胞生长因子（bFGF），胰岛素，胆囊收缩素（CCK）]诱导的一氧化氮（NO）的生产和涉及的细胞内信号传导的影响，使用中国仓鼠卵巢-K1细胞稳定转染个别SSTR 1-SSTR 4。bFGF和胰岛素分别通过产生神经酰胺或Akt依赖的内皮型一氧化氮合酶磷酸化来诱导内皮型一氧化氮合酶活性。CCK以Ca++依赖的方式调节神经元型一氧化氮合酶的活性。SST通过SST受体1（SSTR 1）、SSTR 2和SSTR 3抑制bFGF刺激的NO产生，通过SSTR 2和SSTR 3抑制CCK刺激的NO产生。在所有的细胞系中，SST处理没有改变胰岛素诱导的NO合成。SSTR 4激活对任何测试的刺激都无效。对bFGF诱导的NO产生的影响来自受体磷酸化和神经酰胺合成的下游。SSTR 2和-3对CCK活性的影响与细胞内Ca++动员的抑制有关，而对胰岛素的影响的缺乏是由于SST对Akt磷酸化的缺乏。这些数据，确定第一次选择性受体亚型抑制作用的SST对NO的产生，可能会打开新的前景，在使用SST激动剂来控制肿瘤血管生成。
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.