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Repurposing a Prokaryotic Toxin-Antitoxin System for the Selective Killing of Oncogenically Stressed Human Cells
Mark A Preston1, Belén Pimentel1, Camino Bermejo-Rodríguez1
1MRC Cancer Cell Unit. Hutchison/MRC Research Centre , Hills Road, Cambridge CB2 0XZ, U.K.
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.
Insights
Scientists engineered a bacterial toxin-antitoxin system to target cancer cells. This synthetic system selectively kills human cells with specific oncogenic stress, offering a new approach for personalized cancer therapy.
Area of Science:
- Molecular Biology
- Synthetic Biology
- Cancer Research
Background:
- Prokaryotic toxin-antitoxin systems regulate cellular processes.
- Bacterial toxins like Kid can induce apoptosis in mammalian cells.
- Existing cancer therapies often face challenges with off-target effects.
Purpose of the Study:
- To engineer a bacterial toxin-antitoxin system for selective cancer cell killing.
- To develop a synthetic system that responds to oncogenic stress in human cells.
- To create a novel platform for personalized anticancer strategies.
Main Methods:
- Engineered the bacterial Kid/Kis toxin-antitoxin pair.
- Modified the antitoxin (Kis) for selective degradation in human cells expressing E6 oncoprotein.
- Developed a synthetic system that is activated by oncogenic stress.
Main Results:
- The engineered system functions autonomously in human cells.
- Cells with oncogenic stress are killed by the Kid toxin.
- Cells without oncogenic stress are protected by the Kis antitoxin.
Conclusions:
- This engineered toxin-antitoxin system provides a framework for targeted cancer therapy.
- The system demonstrates selective killing of cancer cells, minimizing off-target effects.
- This approach offers a novel strategy for personalized anticancer treatments.
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