Abstract 1289: The recombinant kringle domain of urokinase plasminogen activator (uPA) inhibits VEGF165-induced proliferation of HUVEC cells

Abstract

Abstract Angiogenesis is associated with tumor growth, invasion and metastasis. Many growth factors and cytokines are engaged in angiogenesis. Among them, vascular endothelial growth factor (VEGF) is one of the most potent and specific angiogenic factors and stimulates endothelial cell proliferation, protease expression, migration and subsequent differentiation to form new vessels. It has been previously revealed that the recombinant kringle domain of urokinase plasminogen activators (uPA) (UK1) exerts antiangiogenic activity against VEGF-induced angiogenesis using in vitro or in vivo model. In this study, we explored molecular signaling mechanisms involved in this activity. The antiangiogenic mechanism of UK1 was investigated in vitro by measuring phosphorylation levels of VEGF signaling proteins. VEGF165 stimulates the phosphorylation of VEGF/VEGFR2 signal molecules, and pre-treatment with UK1 blocked not only VEGF-induced phosphorylation of VEGFR2 but also phosphorylations of downstream signaling proteins, such as Erk and Akt. In addition, VEGF induced secretion of MMP2 in HUVEC, which efficiently suppressed by UK1 pre-treatment. However, mRNA levels of MMP2 as well as of MMP9, Timp1 and Timp2 remained unaffected by UK1. Overall, our findings suggest that UK1 inhibits VEGF-induced proliferation and migration of HUVEC by suppressing VEGF/VEGFR2-mediated angiogenic signals and MMP2 activity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1289.