title: Targeted delivery of an ADP-ribosylating bacterial toxin into cancer cells.
abstract: 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.
authors.affiliation: Institute for Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Albertstr. 25, 79104 Freiburg, Germany.
authors.forename: N-I
authors.initials: NI
authors.lastname: Zahaf
authors.affiliation: Institute for Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Albertstr. 25, 79104 Freiburg, Germany.
authors.forename: A E
authors.initials: AE
authors.lastname: Lang
authors.affiliation: Institute for Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Albertstr. 25, 79104 Freiburg, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Kaiser
authors.affiliation: Institute of Surgical Pathology, Medical Center - University of Freiburg, Breisacherstr. 115a, 79106 Freiburg, Germany.|Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: C D
authors.initials: CD
authors.lastname: Fichter
authors.affiliation: Institute of Surgical Pathology, Medical Center - University of Freiburg, Breisacherstr. 115a, 79106 Freiburg, Germany.|Faculty of Medicine, University of Freiburg, Freiburg, Germany.|Comprehensive Cancer Center, Freiburg, Germany.|BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiberg, Germany.|German Consortium for Translational Cancer Research (DKTK), Freiberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Lassmann
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA02115, USA.
authors.forename: A
authors.initials: A
authors.lastname: McCluskey
authors.affiliation: Institute for Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Albertstr. 25, 79104 Freiburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Augspach
authors.affiliation: Institute for Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Albertstr. 25, 79104 Freiburg, Germany.|Faculty of Medicine, University of Freiburg, Freiburg, Germany.|BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiberg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Aktories
authors.affiliation: Institute for Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Albertstr. 25, 79104 Freiburg, Germany.|Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Schmidt
mesh_terms: D036002:ADP Ribose Transferases / Q000737:chemistry* / Q000235:genetics; D000074744:ADP-Ribosylation / Q000235:genetics*; D008841:Actin Cytoskeleton / Q000235:genetics / Q000382:microbiology; D000942:Antigens, Bacterial / Q000737:chemistry / Q000494:pharmacology; D001427:Bacterial Toxins / Q000737:chemistry* / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000737:chemistry / Q000235:genetics; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020637:Photorhabdus / Q000737:chemistry; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000235:genetics
chemical_list: D036002:ADP Ribose Transferases; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; C030325:anthrax toxin; C512478:EGFR protein, human; C508053:ERBB2 protein, human