title: Repurposing a Prokaryotic Toxin-Antitoxin System for the Selective Killing of Oncogenically Stressed Human Cells.
abstract: Prokaryotes express intracellular toxins that pass unnoticed to carrying cells until coexpressed antitoxin partners are degraded in response to stress. Although not evolved to function in eukaryotes, one of these toxins, Kid, induces apoptosis in mammalian cells, an effect that is neutralized by its cognate antitoxin, Kis. Here we engineered this toxin-antitoxin pair to create a synthetic system that becomes active in human cells suffering a specific oncogenic stress. Inspired by the way Kid becomes active in bacterial cells, we produced a Kis variant that is selectively degraded in human cells expressing oncoprotein E6. The resulting toxin-antitoxin system functions autonomously in human cells, distinguishing those that suffer the oncogenic insult, which are killed by Kid, from those that do not, which remain protected by Kis. Our results provide a framework for developing personalized anticancer strategies avoiding off-target effects, a challenge that has been hardly tractable by other means thus far.
authors.affiliation: MRC Cancer Cell Unit. Hutchison/MRC Research Centre , Hills Road, Cambridge CB2 0XZ, U.K.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Preston
authors.affiliation: MRC Cancer Cell Unit. Hutchison/MRC Research Centre , Hills Road, Cambridge CB2 0XZ, U.K.
authors.forename: Belén
authors.initials: B
authors.lastname: Pimentel
authors.affiliation: MRC Cancer Cell Unit. Hutchison/MRC Research Centre , Hills Road, Cambridge CB2 0XZ, U.K.
authors.forename: Camino
authors.initials: C
authors.lastname: Bermejo-Rodríguez
authors.affiliation: MRC Cancer Cell Unit. Hutchison/MRC Research Centre , Hills Road, Cambridge CB2 0XZ, U.K.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dionne
authors.affiliation: MRC Cancer Cell Unit. Hutchison/MRC Research Centre , Hills Road, Cambridge CB2 0XZ, U.K.
authors.forename: Alice
authors.initials: A
authors.lastname: Turnbull
authors.affiliation: MRC Cancer Cell Unit. Hutchison/MRC Research Centre , Hills Road, Cambridge CB2 0XZ, U.K.|Andalusian Centre for Nanomedicine and Biotechnology (BIONAND), Parque Tecnológico de Andalucı́a , C/Severo Ochoa 35, 29590 Campanillas, Málaga, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: de la Cueva-Méndez
mesh_terms: D000992:Antitoxins / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D001427:Bacterial Toxins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics / Q000254:growth & development; D005260:Female; D005818:Genetic Engineering / Q000379:methods*; D057809:HEK293 Cells; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism; D025821:Polyubiquitin / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000473:pathology* / Q000821:virology
chemical_list: D000992:Antitoxins; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004268:DNA-Binding Proteins; C068651:E6 protein, Human papillomavirus type 16; C052603:E6 protein, Human papillomavirus type 18; C068353:Kid protein, Bacteria; C068354:Kis protein, Bacteria; D009856:Oncogene Proteins, Viral; D011994:Recombinant Proteins; D012097:Repressor Proteins; D025821:Polyubiquitin
keywords: HPV; Kid-Kis; cancer cell killing; gene therapy; protein therapy; smart therapeutic system; toxin-antitoxin system