title: Efficient inhibition of tumor angiogenesis and growth by a synthetic peptide blocking S100A4-methionine aminopeptidase 2 interaction.
abstract: The prometastatic calcium-binding protein, S100A4, is expressed in endothelial cells, and its downregulation markedly suppresses tumor angiogenesis in a xenograft cancer model. Given that endothelial S100A4 can be a molecular target for inhibiting tumor angiogenesis, we addressed here whether synthetic peptide capable of blocking S100A4-effector protein interaction could be a novel antiangiogenic agent. To examine this hypothesis, we focused on the S100A4-binding domain of methionine aminopeptidase 2, an effector protein, which plays a role in endothelial cell growth. Overexpression of the domain in mouse endothelial MSS31 cells reduced DNA synthesis, and the corresponding synthetic peptide (named NBD) indeed interacted with S100A4 and inhibited capillary formation in vitro and new blood vessel formation in vivo. Intriguingly, a single intra-tumor administration of the NBD peptide in human prostate cancer xenografts significantly reduced vascularity, resulting in tumor regression. Mechanistically, the NBD peptide enhanced assembly of nonmuscle myosin IIA filaments along with Ser1943 phosphorylation, stimulated formation of focal adhesions without phosphorylation of focal adhesion kinase, and provoked G1/S arrest of the cell cycle. Altogether, the NBD peptide is a potent inhibitor for tumor angiogenesis, and is the first example of an anticancer peptide drug developed on the basis of an endothelial S100A4-targeted strategy.
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute , Tokyo, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ochiya
authors.affiliation: Department of Life Science, Shimane University School of Medicine , Izumo, Japan.
authors.forename: Keizo
authors.initials: K
authors.lastname: Takenaga
authors.affiliation: The Institute of Medical Science, The University of Tokyo , Tokyo, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Asagiri
authors.affiliation: Department of Medical Genome Sciences, Laboratory of Tumor Cell Biology, Graduate School of Frontier Sciences, The University of Tokyo , Tokyo, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Nakano
authors.affiliation: Department of Medical Genome Sciences, Laboratory of Tumor Cell Biology, Graduate School of Frontier Sciences, The University of Tokyo , Tokyo, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Satoh
authors.affiliation: Department of Medical Genome Sciences, Laboratory of Tumor Cell Biology, Graduate School of Frontier Sciences, The University of Tokyo , Tokyo, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: The Institute of Medical Science, The University of Tokyo , Tokyo, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Imajoh-Ohmi
authors.affiliation: The Institute of Medical Science, The University of Tokyo , Tokyo, Japan ; Department of Medical Genome Sciences, Laboratory of Tumor Cell Biology, Graduate School of Frontier Sciences, The University of Tokyo , Tokyo, Japan.
authors.forename: Hideya
authors.initials: H
authors.lastname: Endo