Somatostatin receptors 1, 2, and 5 cooperate in the somatostatin inhibition of C6 glioma cell proliferation in vitro via a phosphotyrosine phosphatase-η-dependent inhibition of extracellularly regulated kinase-1/2
Somatostatin receptors 1, 2, and 5 cooperate in the somatostatin inhibition of C6 glioma cell proliferation in vitro via a phosphotyrosine phosphatase-η-dependent inhibition of extracellularly regulated kinase-1/2
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DOI：
10.1210/en.2007-1762
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发表时间：
2008-09-01
期刊：
影响因子：
4.8
通讯作者：
Florio, Tullio
中科院分区：
文献类型：
--
作者：
Barbieri, Federica;Pattarozzi, Alessandra;Florio, Tullio
Somatostatin inhibits cell proliferation through the activation of five receptors (SSTR1-5) expressed in normal and cancer cells.我们分析了个体 SSTR 在生长抑素在 C6 大鼠神经胶质瘤细胞中的抗增殖活性中的作用。生长抑素剂量依赖性地抑制 C6 增殖，BIM-23745、BIM-23120、BIM-23206（SSTR1、-2 和 -5 的激动剂）和奥曲肽模仿了这种效果，但具有不同的功效或效力。 SSTR3 的激活是无效的，尽管所有 SSTR 都具有功能活性，如 cAMP 产生的抑制所证明的那样。所有 SSTR 通过激活磷酸酪氨酸磷酸酶 PTP eta 和抑制 ERK1/2 来诱导细胞抑制作用。为了了解 SSTR 亚型之间可能存在的协同作用，我们测试了两种激动剂（SSTR1 + 2 或 SSTR2 + 5）或双功能化合物联合治疗的效果。同时激活 SSTR1 和 SSTR2 会略微提高各个化合物的功效，其 IC50 介于单个受体激活之间。 SSTR2 + 5 激活显示出与单独 SSTR5 激动剂可叠加的响应模式（与 BIM-23120 相比，效力较低，功效较高）。同时激活 SSTR1、-2 和 -5 会产生类似于生长抑素的反应。总之，生长抑素在 C6 细胞中的细胞抑制作用是由 SSTR1、-2 和 -5 通过相同的细胞内途径介导的：激活 PTP eta 并抑制 ERK1/2 活性。生长抑素比单独的激动剂更有效。 SSTR1 和-2 的联合激活在抗增殖活性方面显示出部分协同作用，而SSTR2 和-5 激活则导致类似于SSTR5 效应的反应。
Somatostatin inhibits cell proliferation through the activation of five receptors (SSTR1-5) expressed in normal and cancer cells. We analyzed the role of individual SSTRs in the antiproliferative activity of somatostatin in C6 rat glioma cells. Somatostatin dose-dependently inhibited C6 proliferation, an effect mimicked, with different efficacy or potency, by BIM-23745, BIM-23120, BIM-23206 (agonists for SSTR1, -2, and -5) and octreotide. The activation of SSTR3 was ineffective, although all SSTRs are functionally active, as demonstrated by the inhibition of cAMP production. All SSTRs induced cytostatic effects through the activation of the phosphotyrosine phosphatase PTP eta and the inhibition of ERK1/2. For possible synergism between SSTR subtypes, we tested the effects of the combined treatment with two agonists (SSTR1 + 2 or SSTR2 + 5) or bifunctional compounds. The simultaneous activation of SSTR1 and SSTR2 slightly increased the efficacy of the individual compounds with an IC50 in between the single receptor activation. SSTR2 + 5 activation displayed a pattern of response superimposable to that of the SSTR5 agonist alone (low potency and higher efficacy, as compared with BIM-23120). The simultaneous activation of SSTR1, -2, and -5 resulted in a response similar to somatostatin. In conclusion, the cytostatic effects of somatostatin in C6 cells are mediated by the SSTR1, -2, and -5 through the same intracellular pathway: activation of PTP eta and inhibition of ERK1/2 activity. Somatostatin is more effective than the individual agonists. The combined activation of SSTR1 and -2 shows a partial synergism as far as antiproliferative activity, whereas SSTR2 and -5 activation results in a response resembling the SSTR5 effects.