Endothelial cell surface F1-Fo ATP synthase is active in ATP synthesis and is inhibited by angiostatin

被引:286
作者
Moser, TL
Kenan, DJ
Ashley, TA
Roy, JA
Goodman, MD
Misra, UK
Cheek, DJ
Pizzo, SV
机构
[1] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA
[2] Duke Univ, Med Ctr, Sch Nursing, Durham, NC 27710 USA
关键词
D O I
10.1073/pnas.131067798
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Angiostatin blocks tumor angiogenesis in vivo, almost certainly through its demonstrated ability to block endothelial cell migration and proliferation. Although the mechanism of angiostatin action remains unknown, identification of F-1-F-0 ATP synthase as the major angiostatin-binding site on the endothelial cell surface suggests that ATP metabolism may play a role in the angiostatin response. Previous studies noting the presence of F-1 ATP synthase subunits on endothelial cells and certain cancer cells did not determine whether this enzyme was functional in ATP synthesis. We now demonstrate that all components of the F-1 ATP synthase catalytic core are present on the endothelial cell surface, where they colocalize into discrete punctate structures. The surface-associated enzyme is active in ATP synthesis as shown by dual-label TLC and bioluminescence assays. Both ATP synthase and ATPase activities of the enzyme are inhibited by angiostatin as well as by antibodies directed against the alpha- and beta -subunits of ATP synthase in cell-based and biochemical assays. Our data suggest that angiostatin inhibits vascularization by suppression of endothelial-surface ATP metabolism, which, in turn, may regulate vascular physiology by established mechanisms. We now have shown that antibodies directed against subunits of ATP synthase exhibit endothelial cell-inhibitory activities comparable to that of angiostatin, indicating that these antibodies function as angiostatin mimetics.
引用
收藏
页码:6656 / 6661
页数:6
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