A cellular sensor of reactive oxygen species and its role in drug resistance
Many chemotherapies kill cancer cells by generating reactive oxygen species (ROS), but the proteins these unstable molecules modify, how those modifications affect cells and the roles the modified proteins play in sensitivity or resistance to therapy are not well understood. To address some of these unknowns, researchers led by Ludwig Harvard’s Liron Bar-Peled explored the targets of 11 anticancer drugs using proteomics and CRISPR-based functional genomics methods. They reported in a May issue of Cell evidence of common mechanisms by which ROS-generating drugs target ribosomal proteins to regulate protein translation. Liron and his colleagues focused on a protein named CHK1, inhibitors of which are in clinical development, showing that it is a nuclear hydrogen peroxide (H2O2) sensor that dampens ROS indirectly through the regulation of mitochondrial translation. They found that H2O2 modifies a conserved cysteine within CHK1, causing a structural change that activates its enzymatic activity. Thus activated, CHK1 phosphorylates the mitochondrial single-stranded DNA-binding protein SSBP1, preventing its localization to mitochondria, which in turn leads to the reduction of H2O2 levels in the nucleus. They also showed that this druggable nucleus-to-mitochondria ROS-sensing pathway mediates resistance to platinum-based agents in ovarian cancer models and correlates with shorter time to platinum resistance in patients.