Oxaliplatin disrupts nucleolar function through biophysical disintegration
| Autor: | H. Broder Schmidt, Zane A. Jaafar, B. Erik Wulff, Jason J. Rodencal, Kibeom Hong, Mohammad O. Aziz-Zanjani, Peter K. Jackson, Manuel D. Leonetti, Scott J. Dixon, Rajat Rohatgi, Onn Brandman |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
Cancer [CP]
Medical Physiology colorectal cancer Antineoplastic Agents General Biochemistry Genetics and Molecular Biology Colo-Rectal Cancer Oxaliplatin transcription/ translation inhibitors RNA Polymerase I drug mechanism Genetics Biochemistry and Cell Biology nucleolus phase separation Digestive Diseases Cell Nucleolus Cancer Platinum |
| Zdroj: | Cell reports, vol 41, iss 6 |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2022.111629 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|