Kallistatin, a novel anti-angiogenesis agent, inhibits angiogenesis via inhibition of the NF-κB signaling pathway

Development of a novel angiogenesis inhibitor will be essential for the improvement of therapeutics against cancer. Kallistatin had been recognized as an endogenous angiogenesis inhibitor. Here, we demonstrated kallistatin's strong antiangiogenesis and antimetastasis activity stimulated by breast cancer cells (MCF-7) and its mechanism of action in vitro. The antiangiogenesis effect in vivo was evaluated by chicken chorioallantoic membrane (CAM) neovascularisation. Because of the underlying molecular mechanism of its antiangiogenesis activity remains poorly understood. In this study, we examined whether the NF-kB signaling pathway was involved in the antiangiogenesis and antimetastasis activity of kallistatin. Kallistatin significantly inhibited TNF-alpha-induced nuclear factor-kB activation in a dose-dependent manner. Addition of kallistatin inhibited TNF-alpha induced IkB alpha degradation; phosphorylation of IkB alpha kinase (IKK), nuclear factor-kB-p65 protein; and nuclear translocation of p65/50. Meanwhile, we investigated the effects of kallistatin on the expression of vascular endothelial growth factor (VEGF) and other angiogenesis-related gene in human umbilical vein endothelial cells (HUVECs). We found that kallistatin decreased the expression of VEGF and some angiogenesis-related genes, which promoted angiogenesis in cancer. Taken together, we suggested that kallistatin would inhibit tumor angiogenesis via inhibition of the NF-kB signaling pathway and finally abrogate NF-kB-dependent gene expression. All the results revealed that kallistatin would have potential as a novel. (c) 2014 Elsevier Masson SAS. All rights reserved.