Systematic identification of anticancer drug targets reveals a nucleus-to-mitochondria ROS-sensing pathway

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.