Showing papers by "Jun-ichi Hanai published in 2002"

Endostatin is a potential inhibitor of Wnt signaling

Abstract: Endostatin (ES) is a fragment of collagen XVIII that possesses antiangiogenic activity. To gain insight into ES-mediated signaling, we studied the effects of ES RNA on Xenopus embryogenesis and observed developmental abnormalities consistent with impaired Wnt signaling. ES RNA blocked the axis duplication induced by β-catenin, partially suppressed Wnt-dependent transcription, and stimulated degradation of both wild-type and “stabilized” forms of β-catenin, the latter suggesting that ES signaling does not involve glycogen synthase kinase 3. Moreover, ES uses a pathway independent of the Siah1 protein in targeting β-catenin for proteasome-mediated degradation. ES failed to suppress the effects of T cell–specific factor (TCF)-VP16 (TVP), a constitutive downstream transcriptional activator that acts independently of β-catenin. Importantly, these data were replicated in endothelial cells and also in the DLD-1 colon carcinoma cells with the mutated adenomatous polyposis coli protein. Finally, suppression of endothelial cell migration and inhibition of cell cycle by ES were reversed by TVP. Though high levels of ES were used in both the Xenopus and endothelial cell studies and the effects on β-catenin signaling were modest, these data argue that at pharmacological concentrations ES may impinge on Wnt signaling and promote β-catenin degradation.

Cellular Actions and Signaling by Endostatin

Abstract: The malignant transformation of a normal cell into a cancer cell requires no vasculature. Growth of solid tumors, however, requires angiogenesis to provide oxygen and nutrients to support cell proliferation. The switch from an avascular to a vascular phenotype is typically associated with acceleration of tumor growth. Antiangiogenic therapy, starving a tumor of its blood supply, is an attractive addition to the anticancer armamentarium. Animal tests of antiangiogenic therapy have shown remarkable potential. Initial human trials have proven antiangiogenic therapy to be remarkably nontoxic. Numerous antiangiogenic agents have been isolated as proteolytic fragments of endogenous polypeptides of the extracellular matrix. Endostatin was the first such antiangiogenic protein described and its potent antitumor effects in mice have generated wide interest. This review summarizes recent advances in endostatin biology and highlights new results on the cellular and subcellular mechanisms of endostatin action.