Somatostatin inhibits tumor angiogenesis and growth via somatostatin receptor-3-mediated regulation of endothelial nitric oxide synthase and mitogen-activated protein kinase activities
Somatostatin inhibits tumor angiogenesis and growth via somatostatin receptor-3-mediated regulation of endothelial nitric oxide synthase and mitogen-activated protein kinase activities
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DOI：
10.1210/en.2002-220949
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发表时间：
2003-04-01
期刊：
影响因子：
4.8
通讯作者：
Albini, A
中科院分区：
文献类型：
--
作者：
Florio, T;Morini, M;Albini, A
据报道，生长抑素通过抗血管生成活性抑制卡波西肉瘤（KS）细胞（KS- imm）异种移植物。在这里，我们发现生长抑素阻断已建立的KS-Imm肿瘤的生长，其疗效与阿霉素（一种临床有效的细胞毒性药物）相同。虽然KS-Imm细胞不表达生长抑素受体（SSTRs），但内皮细胞表达几种SSTRs，特别是SSTR3。我们研究了生长抑素抑制血管生成的分子机制和受体特异性。matrigel海绵实验中，生长抑素显著抑制体内血管生成；这种抑制作用被SSTR3激动剂L-796778模拟，并被SSTR3拮抗剂BN81658逆转，表明SSTR3参与其中。体外实验表明，生长抑素通过抑制生长因子刺激的MAPK和内皮一氧化氮（NO）合成酶（eNOS）活性直接影响不同内皮细胞系的增殖。BN81658逆转了生长抑素对细胞增殖、NO生成和MAPK活性的抑制作用，表明体外生长抑素的作用需要SSTR3激活。最后，体内血管生成实验表明，eNOS抑制是生长抑素抗血管生成作用的先决条件，因为高浓度硝普钠（NO供体）可以消除生长抑素的作用。总之，我们证明了生长抑素是一种强大的体内抗肿瘤药物，通过sstr3介导的eNOS和MAPK活性抑制抑制肿瘤血管生成。
Somatostatin was reported to inhibit Kaposi's sarcoma (KS) cell (KS-Imm) xenografts through an antiangiogenic activity. Here, we show that somatostatin blocks growth of established KS-Imm tumors with the same efficacy as adriamycin, a clinically effective cytotoxic drug. Whereas KS-Imm cells do not express somatostatin receptors (SSTRs), endothelial cells express several SSTRs, in particular SSTR3. We investigated the molecular mechanisms and receptor specificity of somatostatin inhibition of angiogenesis. Somatostatin significantly inhibited angiogenesis in vivo in the matrigel sponge assay; this inhibition was mimicked by the SSTR3 agonist L-796778 and reversed by the SSTR3 antagonist BN81658, demonstrating involvement of SSTR3. In vitro experiments showed that somatostatin directly affected different endothelial cell line proliferation through a block of growth-factor-stimulated MAPK and endothelial nitric oxide (NO) synthase (eNOS) activities. BN81658 reversed somatostatin inhibition of cell proliferation, NO production, and MAPK activity, indicating that SSTR3 activation is required for the effects of somatostatin in vitro. Finally in vivo angiogenesis assays demonstrated that eNOS inhibition was a prerequisite for the antiangiogenic effects of somatostatin, because high concentrations of sodium nitroprusside, an NO donor, abolished the somatostatin effects. In conclusion, we demonstrate that somatostatin is a powerful antitumor agent in vivo that inhibits tumor angiogenesis through SSTR3-mediated inhibition of both eNOS and MAPK activities.