Gho Y S, Lee J E, Oh K S, Bae D G, Chae C B
Department of Life Science, Pohang University of Science and Technology, Korea.
Cancer Res. 1997 Sep 1;57(17):3733-40.
Angiogenesis is essential for tumor growth and metastasis. Here, we have developed a peptide antagonist of human angiogenin, which is a potent and tumor-associated angiogenic factor. ANI-E peptide was derived from the phage clone, which binds to angiogenin via the disulfide-constrained octapeptide epitope that is displayed on its surface, and is displaced by actin. Disulfide-constrained ANI-E peptide inhibits the interaction of angiogenin with actin, which is regarded as the angiogenin-binding protein on the surface of endothelial cells, without any visible effect on the ribonucleolytic activity of angiogenin. The peptide also inhibits the neovascularization that is induced by angiogenin in the chick chorioallantoic membrane assay. The antiangiogenic activity of the peptide is specific for angiogenin because the peptide does not have any apparent effect on embryonic angiogenesis or the preexisting blood vessels. The disulfide bond and the glutamic acid inside the disulfide ring of ANI-E peptide are indispensable for its antiangiogenin activity. Furthermore, ANI-E peptide blocks the angiogenesis that is induced by the angiogenin-secreting PC3 human prostate adenocarcinoma cells, without any direct effect on the proliferation, as well as the adhesion of PC3 cells to angiogenin. Therefore, the inhibition of the tumor-induced angiogenesis by ANI-E peptide is most likely caused by the neutralization of the extracellular angiogenin that is secreted by PC3 cells. On the basis of our results, ANI-E peptide may be effective for the treatment of various human tumors that secrete angiogenin. Our results also strongly support the hypothesis that the interaction of angiogenin with the cell surface actin-like protein is essential for the biological action of angiogenin, and angiogenin has an essential role in tumor-induced angiogenesis.
血管生成对于肿瘤生长和转移至关重要。在此，我们开发了一种人血管生成素的肽拮抗剂，血管生成素是一种强效的、与肿瘤相关的血管生成因子。ANI-E肽源自噬菌体克隆，它通过其表面展示的二硫键约束八肽表位与血管生成素结合，并被肌动蛋白取代。二硫键约束的ANI-E肽抑制血管生成素与肌动蛋白的相互作用，肌动蛋白被认为是内皮细胞表面的血管生成素结合蛋白，而对血管生成素的核糖核酸酶活性没有任何明显影响。该肽还在鸡胚绒毛尿囊膜试验中抑制血管生成素诱导的新血管形成。该肽的抗血管生成活性对血管生成素具有特异性，因为该肽对胚胎血管生成或已有的血管没有任何明显影响。ANI-E肽二硫键环内的二硫键和谷氨酸对于其抗血管生成素活性是不可或缺的。此外，ANI-E肽阻断血管生成素分泌性PC3人前列腺腺癌细胞诱导的血管生成，而对PC3细胞的增殖以及PC3细胞与血管生成素的黏附没有任何直接影响。因此，ANI-E肽对肿瘤诱导的血管生成的抑制很可能是由PC3细胞分泌的细胞外血管生成素的中和作用引起的。基于我们的结果，ANI-E肽可能对治疗分泌血管生成素的各种人类肿瘤有效。我们的结果也有力地支持了以下假设：血管生成素与细胞表面肌动蛋白样蛋白的相互作用对于血管生成素的生物学作用至关重要，并且血管生成素在肿瘤诱导的血管生成中起重要作用。
