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.