Endothelial cell surface ATP synthase-triggered caspase-apoptotic pathway is essential for K1-5-induced antiangiogenesis

Niina Veitonmäki, Renhai Cao, Lin Hua Wu, Tammy L. Moser, Bo Li, Salvatore V. Pizzo, Boris Zhivotovsky, Yihai Cao

Research output: Contribution to journalArticlepeer-review

76 Citations (Scopus)

Abstract

We have recently reported the identification of kringle 1-5 (K1-5) of plasminogen as a potent and specific inhibitor of angiogenesis and tumor growth. Here, we show that K1-5 bound to endothelial cell surface ATP synthase and triggered caspase-mediated endothelial cell apoptosis. Induction of endothelial apoptosis involved sequential activation of caspases-8, -9, and -3. Administration of neutralizing antibodies directed against the α- and β-subunits of ATP synthase to endothelial cells attenuated activation of these caspases. Furthermore, inhibitors of caspases-3, -8, and -9 also remarkably blocked K1-5-induced endothelial cell apoptosis and antiangiogenic responses. In a mouse tumor model, we show that caspase-3 inhibitors abolished the antitumor activity of K1-5 by protecting the tumor vasculature undergoing apoptosis. These results suggest that the specificity of the antiendothelial effect of K1-5 is attributable, at least in part, to its interaction with the endothelial cell surface ATP synthase and that the caspase-mediated endothelial apoptosis is essential for the angiostatic activity of K1-5. Thus, our findings provide a mechanistic insight with respect to the angiostatic action and signaling pathway of K1-5 and angiostatin.

Original languageEnglish
Pages (from-to)3679-3686
Number of pages8
JournalCancer Research
Volume64
Issue number10
DOIs
Publication statusPublished - 2004 May 15

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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