title: Targeted Inhibition of Glutamine-Dependent Glutathione Metabolism Overcomes Death Resistance Induced by Chronic Cycling Hypoxia.
abstract: Tumor hypoxia is a major biological factor causing poor patient outcome. Evidence is increasing that improved protection against reactive oxygen species (ROS) participates in therapy resistance of chronically hypoxic cancer cells. We aimed at characterizing the relevance of improved ROS defense for radiation resistance of cancer cells with tolerance to cycling anoxia/re-oxygenation stress ("anoxia-tolerant") and at designing rational treatment strategies for overcoming the resulting therapy resistance by targeting the underlying mechanisms identified in an in vitro model.
  
  
  
  We demonstrate that chronic exposure of NCH-H460 lung adenocarcinoma, DU145 prostate cancer, and T98G glioblastoma cells to cycling anoxia/re-oxygenation stress induced upregulation of the aspartate-aminotransferase glutamic-oxaloacetic transaminase (GOT1), particularly in RAS-driven anoxia-tolerant NCI-H460 cells. Altered glutamine utilization of the anoxia-tolerant cancer cells contributed to the observed decrease in cellular ROS levels, the increase in cellular glutathione levels, and improved cell survival on ROS-inducing treatments, including exposure to ionizing radiation. Importantly, targeting glutamine-dependent antioxidant capacity or glutathione metabolism allowed us to hit anoxia-tolerant cancer cells and to overcome their increased resistance to radiation-induced cell death. Targeting glutathione metabolism by Piperlongumine also improved the radiation response of anoxia-tolerant NCI-H460 cells in vivo.
  
  
  
  Improved antioxidant capacity downstream of up-regulated GOT1-expression is a characteristic of anoxia-tolerant cancer cells and is predictive for a specific vulnerability to inhibition of glutamine utilization or glutathione metabolism, respectively.
  
  
  
  Unraveling the molecular alterations underlying improved ROS defense of anoxia-tolerant cancer cells allows the design of rational strategies for overcoming radiation resistance caused by tumor cell heterogeneity in hypoxic tumors. Antioxid. Redox Signal. 25, 89-107.
authors.affiliation: 1 Institute of Cell Biology (Cancer Research), University Hospital Essen , Essen, Germany .
authors.forename: Johann
authors.initials: J
authors.lastname: Matschke
authors.affiliation: 1 Institute of Cell Biology (Cancer Research), University Hospital Essen , Essen, Germany .
authors.forename: Helena
authors.initials: H
authors.lastname: Riffkin
authors.affiliation: 1 Institute of Cell Biology (Cancer Research), University Hospital Essen , Essen, Germany .
authors.forename: Diana
authors.initials: D
authors.lastname: Klein
authors.affiliation: 2 Institute of Applied Biotechnology (IAB), University of Applied Sciences , Biberach, Germany .
authors.forename: René
authors.initials: R
authors.lastname: Handrick
authors.affiliation: 3 Department of Radiotherapy, University Hospital Essen , Essen, Germany .
authors.forename: Lutz
authors.initials: L
authors.lastname: Lüdemann
authors.affiliation: 4 Institute of Physiology, University Hospital Essen , Essen, Germany .
authors.forename: Eric
authors.initials: E
authors.lastname: Metzen
authors.affiliation: 5 Department of Computer Science and Biology & Lokey Center for Life Science and Engineering, Technion, Haifa, Israel .
authors.forename: Tomer
authors.initials: T
authors.lastname: Shlomi
authors.affiliation: 3 Department of Radiotherapy, University Hospital Essen , Essen, Germany .
authors.forename: Martin
authors.initials: M
authors.lastname: Stuschke
authors.affiliation: 1 Institute of Cell Biology (Cancer Research), University Hospital Essen , Essen, Germany .
authors.forename: Verena
authors.initials: V
authors.lastname: Jendrossek
mesh_terms: D000220:Adaptation, Biological / Q000235:genetics / Q000528:radiation effects; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D024443:Aspartate Aminotransferase, Cytoplasmic / Q000235:genetics / Q000378:metabolism; D016923:Cell Death; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D004148:Dioxolanes / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D005973:Glutamine / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics / Q000528:radiation effects; D011836:Radiation Tolerance / Q000235:genetics; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D010881:Piperidones
chemical_list: D000975:Antioxidants; D024443:Aspartate Aminotransferase, Cytoplasmic; D004148:Dioxolanes; D005973:Glutamine; D005978:Glutathione; D011838:Radiation-Sensitizing Agents; D017382:Reactive Oxygen Species; C498077:piperlongumine; D010881:Piperidones