Targeted delivery of an ADP-ribosylating bacterial toxin into cancer cells
Targeted delivery of an ADP-ribosylating bacterial toxin into cancer cells
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将 ADP 核糖基化细菌毒素靶向递送至癌细胞中
DOI：
10.1038/srep41252
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发表时间：
2017
影响因子：
4.6
通讯作者：
G. Schmidt
中科院分区：
文献类型：
--
作者：
A.E. Lang;L. Kaiser;C.D. Fichter;S. Lassmann;A. McCluskey;A. Augspach;K. Aktories;G. Schmidt
肌动蛋白细胞骨架是细菌毒素的一个有吸引力的目标。来自昆虫细菌病原体发光杆菌的ADP-核糖基转移酶TccC 3修饰肌动蛋白以迫使其聚集。我们打算使用毒素转运蛋白（保护性抗原，PA）将该毒素的催化部分优先转运到癌细胞中，该毒素转运蛋白被重定向到表皮生长因子受体（EGFR）或人EGF受体2（HER 2），这些受体在几种癌细胞中过表达。炭疽毒素的保护性抗原形成了一个小孔，通过这个小孔，两个催化部分（致死因子和水肿因子）或其他蛋白质可以被转运到哺乳动物细胞中。在这里，我们使用PA作为双突变体（N682 A，D 683 A; mPA），其不能结合两种天然炭疽受体。每个突变的单体与EGF或针对人EGF受体2（HER 2）的抗体融合。我们建立了一个细胞模型系统，由两个细胞系组成，分别代表HER 2过表达的食管腺癌（EAC）和EGFR过表达的食管鳞状细胞癌（ESCC）。我们研究了重定向炭疽孔转运TccC 3毒素的特异性和效率，并确定发光光杆菌TccC 3作为适合于开发选择性杀伤癌细胞的靶向毒素的毒素。
The actin cytoskeleton is an attractive target for bacterial toxins. The ADP-ribosyltransferase TccC3 from the insect bacterial pathogenPhotorhabdus luminescencemodifies actin to force its aggregation. We intended to transport the catalytic part of this toxin preferentially into cancer cells using a toxin transporter (Protective antigen, PA) which was redirected to Epidermal Growth Factor Receptors (EGFR) or to human EGF receptors 2 (HER2), which are overexpressed in several cancer cells. Protective antigen of anthrax toxin forms a pore through which the two catalytic parts (lethal factor and edema factor) or other proteins can be transported into mammalian cells. Here, we used PA as a double mutant (N682A, D683A; mPA) which cannot bind to the two natural anthrax receptors. Each mutated monomer is fused either to EGF or to an affibody directed against the human EGF receptor 2 (HER2). We established a cellular model system composed of two cell lines representing HER2 overexpressing esophageal adenocarcinomas (EACs) and EGFR overexpressing esophageal squamous cell carcinomas (ESCCs). We studied the specificity and efficiency of the re-directed anthrax pore for transport of TccC3 toxin and establishedPhotorhabdus luminescenceTccC3 as a toxin suitable for the development of a targeted toxin selectively killing cancer cells.