title: Increased Expression of System xc- in Glioblastoma Confers an Altered Metabolic State and Temozolomide Resistance.
abstract: Glioblastoma multiforme is the most aggressive malignant primary brain tumor in adults. Several studies have shown that glioma cells upregulate the expression of xCT (SLC7A11), the catalytic subunit of system xc-, a transporter involved in cystine import, that modulates glutathione production and glioma growth. However, the role of system xc-in regulating the sensitivity of glioma cells to chemotherapy is currently debated. Inhibiting system xc-with sulfasalazine decreased glioma growth and survival via redox modulation, and use of the chemotherapeutic agent temozolomide together with sulfasalazine had a synergistic effect on cell killing. To better understand the functional consequences of system xc-in glioma, stable SLC7A11-knockdown and -overexpressing U251 glioma cells were generated. Modulation of SLC7A11 did not alter cellar proliferation but overexpression did increase anchorage-independent cell growth. Knockdown of SLC7A11 increased basal reactive oxygen species (ROS) and decreased glutathione generation resulting in increased cell death under oxidative and genotoxic stress. Overexpression of SLC7A11 resulted in increased resistance to oxidative stress and decreased chemosensitivity to temozolomide. In addition, SLC7A11 overexpression was associated with altered cellular metabolism including increased mitochondrial biogenesis, oxidative phosphorylation, and ATP generation. These results suggest that expression of SLC7A11 in the context of glioma contributes to tumorigenesis, tumor progression, and resistance to standard chemotherapy.
  
  
  
  SLC7A11, in addition to redox modulation, appears to be associated with increased cellular metabolism and is a mediator of temozolomide resistance in human glioma, thus making system xC-a potential therapeutic target in glioblastoma multiforme. Mol Cancer Res; 14(12); 1229-42. ©2016 AACR.
authors.affiliation: Department of Neurosciences, City of Hope National Medical Center and Beckman Research Institute, Duarte, California. monika.polewski@gmail.com kaboody@coh.org.|Irell and Manella Graduate School of Biological Sciences, City of Hope National Medical Center and Beckman Research Institute, Duarte, California.
authors.forename: Monika D
authors.initials: MD
authors.lastname: Polewski
authors.affiliation: Department of Neurosciences, City of Hope National Medical Center and Beckman Research Institute, Duarte, California.|Department of Biological Sciences, California State University, San Bernardino, California.
authors.forename: Rosyli F
authors.initials: RF
authors.lastname: Reveron-Thornton
authors.affiliation: Irell and Manella Graduate School of Biological Sciences, City of Hope National Medical Center and Beckman Research Institute, Duarte, California.|Department of Cancer Immunotherapeutics and Tumor Immunology, City of Hope National Medical Center and Beckman Research Institute, Duarte, California.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Cherryholmes
authors.affiliation: Division of Biology, California Institute of Technology, Pasadena, California.
authors.forename: Georgi K
authors.initials: GK
authors.lastname: Marinov
authors.affiliation: Irell and Manella Graduate School of Biological Sciences, City of Hope National Medical Center and Beckman Research Institute, Duarte, California.|Departments of Diabetes Research and Hematology/Hematopoietic Cell Transplantation, City of Hope National Medical Center and Beckman Research Institute, Duarte, California.
authors.forename: Kaniel
authors.initials: K
authors.lastname: Cassady
authors.affiliation: Department of Neurosciences, City of Hope National Medical Center and Beckman Research Institute, Duarte, California. monika.polewski@gmail.com kaboody@coh.org.|Division of Neurosurgery, City of Hope National Medical Center and Beckman Research Institute, Duarte, California.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Aboody
mesh_terms: D027182:Amino Acid Transport System y+ / Q000037:antagonists & inhibitors / Q000235:genetics*; D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics*; D005978:Glutathione; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D017382:Reactive Oxygen Species / Q000378:metabolism; D012460:Sulfasalazine / Q000494:pharmacology*; D000077204:Temozolomide
chemical_list: D027182:Amino Acid Transport System y+; D017382:Reactive Oxygen Species; C118895:SLC7A11 protein, human; D012460:Sulfasalazine; D003606:Dacarbazine; D005978:Glutathione; D000077204:Temozolomide