Targeted delivery of an ADP-ribosylating bacterial toxin into cancer cells

• Published in: Scientific reports Vol. 7; no. 1; p. 41252
• Main Authors: Zahaf , N.-I., Lang, A. E., Kaiser, L., Fichter, C. D., Lassmann, S., McCluskey, A., Augspach, A., Aktories, K., Schmidt, G.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.01.2017; Nature Publishing Group
• Subjects: 13; 631/67/1665; 631/80/2023/2022; 82; 82/80; Actin; Actin Cytoskeleton - genetics; Actin Cytoskeleton - microbiology; Adenosine diphosphate; ADP Ribose Transferases - chemistry; ADP Ribose Transferases - genetics; ADP-Ribosylation - genetics; Anthrax; Antigens; Antigens, Bacterial - chemistry; Antigens, Bacterial - pharmacology; Bacterial Toxins - chemistry; Bacterial Toxins - pharmacology; Cancer; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; Cell Line, Tumor; Cytoskeleton; Edema; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - chemistry; ErbB Receptors - genetics; ErbB-2 protein; Esophageal carcinoma; Esophageal Neoplasms - drug therapy; Esophageal Neoplasms - genetics; Esophageal Neoplasms - pathology; Esophageal Squamous Cell Carcinoma; Esophagus; Gene Expression Regulation - drug effects; Growth factor receptors; Humanities and Social Sciences; Humans; Lethal factor; Luminescence; Mammalian cells; multidisciplinary; Photorhabdus - chemistry; Protective antigen; Receptor, ErbB-2 - chemistry; Receptor, ErbB-2 - genetics; Science; Science (multidisciplinary); Squamous cell carcinoma; Toxins
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep41252

The actin cytoskeleton is an attractive target for bacterial toxins. The ADP-ribosyltransferase TccC3 from the insect bacterial pathogen Photorhabdus luminescence modifies 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 established Photorhabdus luminescence TccC3 as a toxin suitable for the development of a targeted toxin selectively killing cancer cells.