1. Oxaliplatin disrupts nucleolar function through biophysical disintegration
- Author
-
Schmidt, H Broder, Jaafar, Zane A, Wulff, B Erik, Rodencal, Jason J, Hong, Kibeom, Aziz-Zanjani, Mohammad O, Jackson, Peter K, Leonetti, Manuel D, Dixon, Scott J, Rohatgi, Rajat, and Brandman, Onn
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Digestive Diseases ,Cancer ,Genetics ,Colo-Rectal Cancer ,Oxaliplatin ,Platinum ,Cell Nucleolus ,Antineoplastic Agents ,RNA Polymerase I ,CP: Cancer ,colorectal cancer ,drug mechanism ,nucleolus ,phase separation ,transcription/ translation inhibitors ,Medical Physiology ,Biological sciences - Abstract
Platinum (Pt) compounds such as oxaliplatin are among 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. Our data suggest that this biophysical defect leads to cell-cycle arrest, shutdown of Pol I-mediated transcription, and ultimately cell death. We propose that instead of targeting a single molecule, oxaliplatin preferentially partitions into nucleoli, where it modifies nucleolar RNA and proteins. This mechanism provides a general approach for drugging the increasing number of cellular processes linked to biomolecular condensates.
- Published
- 2022