Oxaliplatin kills cells via liquid-liquid demixing of nucleoli
Schmidt, H. B.; Jaafar, Z.; Rodencal, J. J.; Leonetti, M. D.; Dixon, S. J.; Rohatgi, R.; Brandman, O.
Show abstract
Platinum (Pt) compounds such as oxaliplatin are amongst the most commonly prescribed anti-cancer drugs. Despite their considerable clinical impact, the molecular basis of platinum cytotoxicity and cancer specificity remain unclear. Here, we show that oxaliplatin, a backbone for the treatment of colorectal cancer, causes liquid-liquid demixing of nucleoli at clinically-relevant concentrations by interfering with the interaction networks that organize nucleoli. This biophysical defect leads to cell cycle arrest, impaired rRNA processing and shutdown of PolI-mediated transcription, ultimately resulting in cell death. We propose that the mechanism of action of oxaliplatin provides a blueprint for the therapeutic targeting of the increasing number of cellular processes being linked to biomolecular condensates.
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