Oxaliplatin disrupts nucleolar function through biophysical disintegration

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

doi:10.1016/j.celrep.2022.111629

Oxaliplatin disrupts nucleolar function through biophysical disintegration

Cell Rep. 2022 Nov 8;41(6):111629. doi: 10.1016/j.celrep.2022.111629.

Authors

Affiliations

¹ Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA.
² Department of Biology, Stanford University, Stanford, CA, USA.
³ Baxter Laboratory for Stem Cell Biology, Stanford University School of Medicine, Stanford, CA, USA.
⁴ Chan Zuckerberg Biohub, San Francisco, CA, USA.
⁵ Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: rrohatgi@stanford.edu.
⁶ Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: onn@stanford.edu.

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.

Keywords: CP: Cancer; colorectal cancer; drug mechanism; nucleolus; phase separation; transcription/ translation inhibitors.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Antineoplastic Agents* / metabolism
Antineoplastic Agents* / pharmacology
Cell Nucleolus / metabolism
Oxaliplatin / pharmacology
Platinum* / metabolism
RNA Polymerase I / metabolism

Substances

Oxaliplatin
Platinum
Antineoplastic Agents
RNA Polymerase I

Abstract

Publication types

MeSH terms

Substances

Grants and funding