Cell surface expression of nucleolin mediates the antiangiogenic and antitumor activities of kallistatin
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Xiao-Ping Huang1,2,*, Xiao Wang2,*, Xiao-Lan Xie1, Gao-Ping Zhang1, Feng-Jiao Lv1, Wen-Ting Weng1, Fei Qiu2, Zhao-Fa Li2, Jun-Sheng Lin2 and Yong Diao2
1College of Chemical Engineering and Materials Sciences, Quanzhou Normal University, Quanzhou, China
2Institute of Molecular Medicine, Huaqiao University, Quanzhou, China
*These authors contributed equally to this work
Jun-Sheng Lin, email: firstname.lastname@example.org
Yong Diao, email: email@example.com
Keywords: kallistatin; nucleolin; endothelial cell; tumor angiogenesis
Received: September 30, 2017 Accepted: November 20, 2017 Published: December 16, 2017
Kallistatin is a unique serine proteinase inhibitor and heparin-binding protein. A previous study conducted by our group indicated that kallistatin has antiangiogenic and antitumoral activities. In the present study, we report that kallistatin specifically binds to membrane surface-expressed nucleolin with high affinity. Antibody-mediated neutralization or siRNA-induced nucleolin knockdown results in loss of kallistatin suppression of endothelial cell proliferation and migration in vitro and tumor angiogenesis and growth in vivo. In addition, we show that kallistatin is internalized and transported into cell nuclei of endothelial cells via nucleolin. Within the nucleus, kallistatin inhibits the phosphorylation of nucleolin, which is a critical step required for cell proliferation. Thus, we demonstrate that nucleolin is a novel functional receptor of kallistatin that mediates its antiangiogenic and antitumor activities. These findings provide mechanistic insights into the inhibitory effects of kallistatin on endothelial cell growth, tumor cell proliferation, and tumor-related angiogenesis.
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