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Blood, 15 October 2007, Vol. 110, No. 8, pp. 2899-2906.
Prepublished online as a Blood First Edition Paper on July 5, 2007; DOI 10.1182/blood-2007-01-064428.
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Submitted January 22, 2007
Accepted June 15, 2007
Nucleolin is a receptor that mediates antiangiogenic and anti-tumor activity of endostatin
Hubing Shi, Yujie Huang, Hao Zhou, Xiaomin Song, Shaopeng Yuan, Yan Fu, and Yongzhang Luo*
Department of Biological Sciences and Biotechnology, Lab. of Protein Chemistry, Protein Science Lab. of the Ministry of Education, Tsinghua University, Beijing, China
* Corresponding author; email: protein{at}tsinghua.edu.cn.
The exact molecular mechanism of how endostatin inhibits angiogenesis and tumor growth remains uncharacterized. Here we report that endostatin specifically binds to the cell surface nucleolin with high affinity. Blockage of nucleolin by a neutralizing antibody or knockdown of nucleolin by the RNA interference results in loss of anti-endothelial activities of endostatin. Importantly, a neutralizing anti-nucleolin antibody abrogates the antiangiogenic and anti-tumor activities of endostatin in vivo. Nucleolin and endostatin are co-localized on the cell surface of endothelial cells of angiogenic blood vessels in the tumor environment. Finally, we found that endostatin is internalized and transported into cell nuclei of endothelial cell via nucleolin. In the nucleus, the phosphorylation of nucleolin, which is critical for cell proliferation, can be inhibited by endostatin. Our studies demonstrate that nucleolin is a novel functional receptor for endostatin, and mediates the antiangiogenic and anti-tumor activities of endostatin. These findings also provide mechanistic insights of how endostatin specifically inhibits proliferating endothelial cell growth and angiogenesis.
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