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

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.

Keywords: CHK1; chemical proteomics; chemoresistance; mitochondrial translation; nuclear ROS; nucleus-to-mitochondria signaling.