title: AKT-mediated enhanced aerobic glycolysis causes acquired radioresistance by human tumor cells.
abstract: OBJECTIVE
  Cellular radioresistance is a major impediment to effective radiotherapy. Here, we demonstrated that long-term exposure to fractionated radiation conferred acquired radioresistance to tumor cells due to AKT-mediated enhanced aerobic glycolysis.
  
  
  METHODS
  Two human tumor cell lines with acquired radioresistance were established by long-term exposure to fractionated radiation with 0.5 Gy of X-rays. Glucose uptake was inhibited using 2-deoxy-D-glucose, a non-metabolizable glucose analog. Aerobic glycolysis was assessed by measuring lactate concentrations. Cells were then used for assays of ROS generation, survival, and cell death as assessed by annexin V staining.
  
  
  RESULTS
  Enhanced aerobic glycolysis was shown by increased glucose transporter Glut1 expression and a high lactate production rate in acquired radioresistant cells compared with parental cells. Inhibiting the AKT pathway using the AKT inhibitor API-2 abrogated these phenomena. Moreover, we found that inhibiting glycolysis with 2-deoxy-D-glucose suppressed acquired tumor cell radioresistance.
  
  
  CONCLUSIONS
  Long-term fractionated radiation confers acquired radioresistance to tumor cells by AKT-mediated alterations in their glucose metabolic pathway. Thus, tumor cell metabolic pathway is an attractive target to eliminate radioresistant cells and improve radiotherapy efficacy.
authors.affiliation: Department of Environmental Health, National Institute of Public Health, Japan. Electronic address: tsimura@niph.go.jp.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Shimura
authors.affiliation: Department of Pathology, Institute of Development, Aging and Cancer, Tohoku University, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Noma
authors.affiliation: Department of Pathology, Institute of Development, Aging and Cancer, Tohoku University, Japan.
authors.forename: Yui
authors.initials: Y
authors.lastname: Sano
authors.affiliation: Department of Pathology, Institute of Development, Aging and Cancer, Tohoku University, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ochiai
authors.affiliation: Department of Pathology, Institute of Development, Aging and Cancer, Tohoku University, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Oikawa
authors.affiliation: Department of Pathology, Institute of Development, Aging and Cancer, Tohoku University, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Fukumoto
authors.affiliation: Department of Environmental Health, National Institute of Public Health, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kunugita
mesh_terms: D000332:Aerobiosis; D016923:Cell Death / Q000187:drug effects; D002747:Chlorpropamide / Q000031:analogs & derivatives / Q000494:pharmacology; D003847:Deoxyglucose / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000096:biosynthesis; D006019:Glycolysis; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D007773:Lactates / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000532:radiotherapy*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011836:Radiation Tolerance / Q000502:physiology / Q000528:radiation effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D000096926:Benzenesulfonamides
chemical_list: D002747:Chlorpropamide; D003847:Deoxyglucose; D005947:Glucose; D051272:Glucose Transporter Type 1; D007773:Lactates; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; C111224:API 2; D000096926:Benzenesulfonamides; C495677:SLC2A1 protein, human
keywords: 2-Deoxy-d-glucose; AKT; Glut1; Glycolysis; Radioresistance