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Mutant Anthrax Toxin B Moiety (Protective Antigen) Inhibits Angiogenesis and Tumor Growth

¹ Vascular Biology Program and Department of Ophthalmology, Children's Hospital, and ² Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts and ³ Department of Chemistry, Clemson University, Clemson, South Carolina

Requests for reprints: Michael S. Rogers, Vascular Biology Program, Children's Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115. Phone: 617-919-2252; Fax: 617-730-0231; E-mail: michael.rogers{at}tch.harvard.edu.

Bacillus anthracis protective antigen (PA), the B subunit of the binary anthrax toxin, binds to the cellular receptors capillary morphogenesis gene 2 protein and tumor endothelial marker 8 with high affinity. Both receptors are expressed on endothelial cells during angiogenesis. We sought to determine whether one could inhibit angiogenesis by interfering with the binding of these receptors to their endogenous ligands. Here, we show that wild-type PA inhibits both vascular endothelial growth factor–induced and basic fibroblast growth factor–induced angiogenesis at moderate but statistically significant levels. Structure-activity studies identified a PA mutant that exhibited markedly enhanced inhibition of angiogenesis and also inhibited tumor growth in vivo. This mutant, PA^SSSR, is unable to undergo normal cellular processing and, thus, remains bound to the surface receptor. Further mutation of PA^SSSR so that it does not bind to these cell surface receptors abolished its ability to inhibit angiogenesis. We conclude that high-affinity anthrax toxin receptor (ATR) ligands, such as PA and PA^SSSR, are angiogenesis inhibitors and that ATRs are useful targets for antiangiogenic therapy. These results also suggest that endothelial cell-binding proteins from additional pathogens may inhibit angiogenesis and raise the question of the role of such inhibition in pathogenesis. [Cancer Res 2007;67(20):9980–5]

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