Mutant anthrax toxin B moiety (protective antigen) inhibits angiogenesis and tumor growth

Cancer Res. 2007 Oct 15;67(20):9980-5. doi: 10.1158/0008-5472.CAN-07-0829.

Abstract

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, PASSSR, is unable to undergo normal cellular processing and, thus, remains bound to the surface receptor. Further mutation of PASSSR 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 PASSSR, 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.

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Antigens, Bacterial / genetics
  • Antigens, Bacterial / metabolism
  • Antigens, Bacterial / pharmacology*
  • Bacterial Toxins / genetics
  • Bacterial Toxins / metabolism
  • Bacterial Toxins / pharmacology*
  • Carcinoma, Lewis Lung / blood supply*
  • Carcinoma, Lewis Lung / drug therapy*
  • Cell Growth Processes / drug effects
  • Cornea / blood supply
  • Corneal Neovascularization / chemically induced
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Fibroblast Growth Factor 2 / antagonists & inhibitors
  • Humans
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Microfilament Proteins
  • Mutation
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / metabolism
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / pathology
  • Neovascularization, Physiologic / drug effects
  • Receptors, Cell Surface / biosynthesis
  • Receptors, Cell Surface / metabolism
  • Receptors, Peptide
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors

Substances

  • ANTXR1 protein, human
  • ANTXR2 protein, human
  • Angiogenesis Inhibitors
  • Antigens, Bacterial
  • Bacterial Toxins
  • Membrane Proteins
  • Microfilament Proteins
  • Neoplasm Proteins
  • Receptors, Cell Surface
  • Receptors, Peptide
  • Vascular Endothelial Growth Factor A
  • anthrax toxin
  • Fibroblast Growth Factor 2