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Updated: Jul 30, 2025
An Automated Differential Nuclear Staining Assay for Accurate Determination of Mitocan Cytotoxicity
Published on: May 12, 2020
Systematic identification of anticancer drug targets reveals a nucleus-to-mitochondria ROS-sensing pathway
Junbing Zhang1, Claire M Simpson2, Jacqueline Berner1
1Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
Abstract:
Multiple anticancer drugs have been proposed to cause cell death, in part, by increasing the steady-state levels of cellular reactive oxygen species (ROS). However, for most of these drugs, exactly how the resultant ROS function and are sensed is poorly understood. It remains unclear which proteins the ROS modify and their roles in drug sensitivity/resistance. To answer these questions, we examined 11 anticancer drugs with an integrated proteogenomic approach identifying not only many unique targets but also shared ones-including ribosomal components, suggesting common mechanisms by which drugs regulate translation. We focus on CHK1 that we find is a nuclear H2O2 sensor that launches a cellular program to dampen ROS. CHK1 phosphorylates the mitochondrial DNA-binding protein SSBP1 to prevent its mitochondrial localization, which in turn decreases nuclear H2O2. Our results reveal a druggable nucleus-to-mitochondria ROS-sensing pathway-required to resolve nuclear H2O2 accumulation and mediate resistance to platinum-based agents in ovarian cancers.
Insights
Anticancer drugs increase reactive oxygen species (ROS), but how cells sense ROS is unclear. This study identifies a nucleus-to-mitochondria pathway involving CHK1 and SSBP1 that resolves ROS accumulation and mediates resistance to platinum-based drugs.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Anticancer drugs can induce cell death by increasing cellular reactive oxygen species (ROS).
- The precise mechanisms by which ROS function and are sensed by cells, including protein modifications and roles in drug sensitivity, remain largely unknown.
- Understanding these pathways is crucial for developing more effective cancer therapies.
Purpose of the Study:
- To elucidate the mechanisms by which anticancer drugs induce cell death via ROS.
- To identify specific proteins modified by ROS and their roles in drug sensitivity and resistance.
- To investigate a novel nucleus-to-mitochondria ROS-sensing pathway.
Main Methods:
- Utilized an integrated proteogenomic approach to analyze the effects of 11 anticancer drugs.
- Identified protein targets modified by ROS.
- Investigated the role of CHK1 as a nuclear ROS sensor and its interaction with SSBP1.
Main Results:
- Identified numerous unique and shared protein targets of ROS, including ribosomal components, suggesting common drug-induced translational regulation mechanisms.
- Discovered that CHK1 acts as a nuclear hydrogen peroxide (H2O2) sensor.
- Found that CHK1 phosphorylates SSBP1, preventing its mitochondrial localization and thereby decreasing nuclear H2O2.
- Revealed a druggable nucleus-to-mitochondria pathway essential for resolving nuclear H2O2 accumulation.
Conclusions:
- A novel nucleus-to-mitochondria ROS-sensing pathway involving CHK1 and SSBP1 regulates cellular ROS levels.
- This pathway is critical for resolving nuclear H2O2 accumulation and mediates resistance to platinum-based anticancer agents in ovarian cancers.
- Targeting this pathway could offer new therapeutic strategies for ovarian cancer treatment.
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