Identification of chemotherapy targets reveals a nucleus-to-mitochondria ROS sensing pathway

Abstract

Multiple chemotherapies are 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. In particular, its unclear which proteins the ROS modify and their roles in chemotherapy sensitivity/resistance. To answer these questions, we examined 11 chemotherapies with an integrated proteogenomic approach identifying many unique targets for these drugs but also shared ones including ribosomal components, suggesting one mechanism by which chemotherapies regulate translation. We focus on CHK1 which we find is a nuclear H2O2 sensor that promotes an anti-ROS cellular program. CHK1 acts by phosphorylating the mitochondrial-DNA binding protein SSBP1, preventing 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, which mediates resistance to platinum-based chemotherapies in ovarian cancers.

DrugMap: A quantitative pan-cancer analysis of cysteine ligandability

“…Subsequent analyses revealed that cysteines that are highly solventaccessible (those lying <2Å from bulk solvent and having a coordination number of <25) or deeply buried (>8Å from bulk solvent with a coordination number of >50) are both disfavored for liganding (Figures 1H, S3D-E). In contrast, cysteines displaying intermediate burial (on average 4-6Å from bulk solvent, with a coordination number of [30][31][32][33][34][35][36][37][38][39][40] are more ligandable (Figures 1H, S3D). We also quantified the nearest amino acid neighbors within a 6Å sphere around ligandable cysteines 32 , resulting in identification of amino acid neighbors associated with ligandability in specific protein families (Figure 1G, S3F).…”

“…In contrast, cysteines displaying intermediate burial (on average 4-6Å from bulk solvent, with a coordination number of [30][31][32][33][34][35][36][37][38][39][40] are more ligandable (Figures 1H, S3D). We also quantified the nearest amino acid neighbors within a 6Å sphere around ligandable cysteines 32 , resulting in identification of amino acid neighbors associated with ligandability in specific protein families (Figure 1G, S3F). We found a general trend for enrichment of basic amino acids near ligandable cysteines, possibly stemming from modulation of cysteine pKa 54 (Figure S3G).…”

“…Most cell lines had a proteomic redox score corresponding to higher levels of liganding, suggesting a more reduced cellular environment (Figure S4I). Focusing on a panel of ovarian cancer cell lines with diverse proteomic redox scores, we found that cells with high levels of heterogeneous cysteine liganding showed higher ROS induction following treatment with auranofin, a drug previously reported to increase ROS levels 32 (Figure S4J). Taken together, these results support the hypothesis that a cancer cell's redox state plays a substantial role in controlling cysteine ligandabilty, and that ligandability itself can be used as surrogate readout for measuring one dimension of the cellular redox environment.…”

“…Concomitant with the rise of covalent inhibitors in the clinic, chemical proteomic methods have now become a popular approach to quantitatively and globally measure cysteine reactivity changes that are dependent on particular metabolic states or physiologies, or are influenced by covalent small-molecule inhibitors [27][28][29][30][31][32][33][34][35] . Advances in these cysteine-focused chemical proteomics approaches now allow for the routine quantification of 10,000+ cysteines per run, and multiplexing technologies have enabled the identification of corresponding targets for hundreds of covalent fragments 17,36,37 .…”

Mitochondrial metabolism-related signature depicts immunophenotype and predicts therapeutic response in testicular germ cell tumors

“…[12] Currently, the mitochondrial pathway has been extensively studied as a potential cancer treatment target. [13] For instance, aloe vera gel polysaccharides induce colon cancer cell death through PINK1/Parkin-mediated mitophagy induced by mitochondrial damage, [14] while Wang et al [15] developed a new imidazo [1,2-a] pyridine derivative that exerts anticancer activity by inducing cell apoptosis through the mitochondrial pathway. Studies have reported that defects in mitochondrial-related genes can regulate the tumor immune metabolic microenvironment.…”