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 anti-angiogenesis and anti-metastasis activity stimulated by breast cancer cells (MCF-7) and its mechanism of action in vitro. The anti-angiogenesis effect in vivo was evaluated by chicken chorioallantoic membrane (CAM) neovascularisation. Because of the underlying molecular mechanism of its anti-angiogenesis activity remains poorly understood. In this study, we examined whether the NF-κB signaling pathway was involved in the anti-angiogenesis and anti-metastasis activity of kallistatin. Kallistatin significantly inhibited TNF-α-induced nuclear factor-κB activation in a dose-dependent manner. Addition of kallistatin inhibited TNF-α induced IκBα degradation; phosphorylation of IκBα kinase (IKK), nuclear factor-κB-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-κB signaling pathway and finally abrogate NF-κB-dependent gene expression. All the results revealed that kallistatin would have potential as a novel.
Institute of Molecular Medicine, Hua-qiao University, 362021 Quan Zhou, China; Xiamen Medicine Research Institute, 361003 Xiamen, China. Electronic address: hkf5306@163.com.
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Huang
Institute of Molecular Medicine, Hua-qiao University, 362021 Quan Zhou, China.
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Huang
Institute of Molecular Medicine, Hua-qiao University, 362021 Quan Zhou, China.
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Xiao
Institute of Molecular Medicine, Hua-qiao University, 362021 Quan Zhou, China.
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Yang
Institute of Molecular Medicine, Hua-qiao University, 362021 Quan Zhou, China; AgResearch, Invermay, Mosgiel, New Zealand. Electronic address: junshenglin@hqu.edu.cn.
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Lin
Institute of Molecular Medicine, Hua-qiao University, 362021 Quan Zhou, China. Electronic address: diaoyong@hqu.edu.cn.
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Diao
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015843:Serpins / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D020533:Angiogenesis Inhibitors; D016328:NF-kappa B; D015843:Serpins; D042461:Vascular Endothelial Growth Factor A; C051324:kallistatin
Angiogenesis; Kallistatin; NF-κB; Tumor