Abstract
Redox cofactor production is integral toward antioxidant generation, clearance of reactive oxygen species, and overall tumor response to ionizing radiation treatment. To identify systems-level alterations in redox metabolism that confer resistance to radiation therapy, we developed a bioinformatics pipeline for integrating multi-omics data into personalized genome-scale flux balance analysis models of 716 radiation-sensitive and 199 radiation-resistant tumors. These models collectively predicted that radiation-resistant tumors reroute metabolic flux to increase mitochondrial NADPH stores and reactive oxygen species (ROS) scavenging. Simulated genome-wide knockout screens agreed with experimental siRNA gene knockdowns in matched radiation-sensitive and radiation-resistant cancer cell lines, revealing gene targets involved in mitochondrial NADPH production, central carbon metabolism, and folate metabolism that allow for selective inhibition of glutathione production and H2O2 clearance in radiation-resistant cancers. This systems approach represents a significant advancement in developing quantitative genome-scale models of redox metabolism and identifying personalized metabolic targets for improving radiation sensitivity in individual cancer patients.
Highlights
Radiation therapy remains a cornerstone of cancer treatment, with more than half of all cancer patients receiving radiation as part of their treatment regimen (Delaney et al, 2005; Miller et al, 2016)
Redox metabolism relies on the oxidation and reduction of electron-carrying molecules such as NADPH, NADH, and glutathione (GSH), which are used as cellular antioxidants and electron donors for metabolic reactions (Lewis et al, 2019; Xiao et al, 2018)
An Automated Bioinformatics Pipeline Integrates MultiOmics Data into Personalized Flux balance analysis (FBA) Models of The Cancer Genome Atlas (TCGA) Patient Tumors The framework for building FBA models of tumor metabolism was initiated with the community-curated Recon3D human metabolic reconstruction (8,401 metabolites, 13,547 reactions, and 3,268 genes; Figure 1A) (Brunk et al, 2018)
Summary
Radiation therapy remains a cornerstone of cancer treatment, with more than half of all cancer patients receiving radiation as part of their treatment regimen (Delaney et al, 2005; Miller et al, 2016). Ionizing radiation therapy results in the generation of reactive oxygen species (ROS) such as superoxide (O2À) and hydrogen peroxide (H2O2), which oxidize the cellular environment and damage cellular structures including DNA (Brady et al, 2013; Cadet and Wagner, 2013; Reisz et al, 2014; Tominaga et al, 2004) Redox cofactors such as NADPH and GSH can be utilized by H2O2-scavenging enzymes to lower cellular levels of ROS (Forshaw et al, 2019; Harris et al, 2015). These cofactors can directly promote DNAdamage repair following oxidative damage, either by reduction of nitrogenous bases or utilization of NAD(P)H for nucleotide
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