Nucleolin is a receptor that mediates antiangiogenic and antitumor activity of endostatin.
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 antiendothelial activities of endostatin. Importantly, a neutralizing antinucleolin antibody abrogates the antiangiogenic and antitumor activities of endostatin in vivo. Nucleolin and endostatin are colocalized 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 antitumor activities of endostatin. These findings also provide mechanistic insights of how endostatin specifically inhibits proliferating endothelial cell growth and angiogenesis.
Shi
Hubing
H
Laboratory of Protein Chemistry, the Protein Science Laboratory of the Ministry of Education, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing, People's Republic of China.
Huang
Yujie
Y
Zhou
Hao
H
Song
Xiaomin
X
Yuan
Shaopeng
S
Fu
Yan
Y
Luo
Yongzhang
Y
D000818:Animals; D018827:Carcinoma, Lewis Lung; D043169:Endostatins / Q000378:metabolism*; D042783:Endothelial Cells / Q000737:chemistry / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000378:metabolism*; D000097796:Nucleolin
D043169:Endostatins; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D000097796:Nucleolin