Mutant anthrax toxin B moiety (Protective antigen) inhibits angiogenesis and tumor growth
Mutant anthrax toxin B moiety (Protective antigen) inhibits angiogenesis and tumor growth
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DOI：
10.1158/0008-5472.can-07-0829
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发表时间：
2007-10-15
期刊：
影响因子：
11.2
通讯作者：
D'Amato, Robert J.
中科院分区：
文献类型：
--
作者：
Rogers, Michael S.;Christensen, Kenneth A.;D'Amato, Robert J.
炭疽杆菌保护性抗原（PA）是炭疽杆菌毒素的B亚单位，与细胞受体毛细血管形态发生基因2蛋白和肿瘤内皮标志物8具有高亲和力。这两种受体在血管生成过程中在内皮细胞上表达。我们试图确定是否可以通过干扰这些受体与其内源性配体的结合来抑制血管生成。在这里，我们表明，野生型PA抑制血管内皮生长因子诱导的和碱性成纤维细胞生长因子诱导的血管生成在中度，但统计学上显着的水平。结构-活性研究鉴定了PA突变体，其表现出显着增强的血管生成抑制，并且还抑制体内肿瘤生长。这种突变体PA（SSSR）不能进行正常的细胞加工，因此仍然与表面受体结合。进一步突变PA（SSSR）使其不与这些细胞表面受体结合，从而消除了其抑制血管生成的能力。我们的结论是，高亲和力炭疽毒素受体（ATR）配体，如PA和PA（SSSR），是血管生成抑制剂，ATR是抗血管生成治疗的有用靶点。这些结果还表明，内皮细胞结合蛋白从其他病原体可能抑制血管生成，并提出了这样的抑制作用的发病机制的问题。
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 factorinduced 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.