title: TIGAR cooperated with glycolysis to inhibit the apoptosis of leukemia cells and associated with poor prognosis in patients with cytogenetically normal acute myeloid leukemia.
abstract: Cancer cells show increased glycolysis and take advantage of this metabolic pathway to generate ATP. The TP53-induced glycolysis and apoptosis regulator (TIGAR) inhibits aerobic glycolysis and protects tumor cells from intracellular reactive oxygen species (ROS)-associated apoptosis. However, the function of TIGAR in glycolysis and survival of acute myeloid leukemia cells remains unclear.
  
  
  
  We analyzed TIGAR expression in cytogenetically normal (CN-) AML patients and the correlations with clinical and biological parameters. In vivo and in vitro, we tested whether glycolysis may induce TIGAR expression and evaluated the combination effect of glycolysis inhibitor and TIGAR knockdown on human leukemia cell proliferation.
  
  
  
  High TIGAR expression was an independent predictor of poor survival and high incidence of relapse in adult patients with CN-AML. TIGAR also showed high expression in multiple human leukemia cell lines and knockdown of TIGAR activated glycolysis through PFKFB3 upregulation in human leukemia cells. Knockdown of TIGAR inhibited the proliferation of human leukemia cells and sensitized leukemia cells to glycolysis inhibitor both in vitro and in vivo. Furthermore, TIGAR knockdown in combination with glycolysis inhibitor 2-DG led leukemia cells to apoptosis. In addition, the p53 activator Nutlin-3α showed a significant combinational effect with TIGAR knockdown in leukemia cells. However, TIGAR expression and its anti-apoptotic effects were uncoupled from overexpression of exogenous p53 in leukemia cells.
  
  
  
  TIGAR might be a predictor of poor survival and high incidence of relapse in AML patients, and the combination of TIGAR inhibitors with anti-glycolytic agents may be novel therapies for the future clinical use in AML patients.
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, 300 Guangzhou Road, Nanjing, 210029, China.
authors.forename: Sixuan
authors.initials: S
authors.lastname: Qian
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, 300 Guangzhou Road, Nanjing, 210029, China.
authors.forename: Jianyong
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, 300 Guangzhou Road, Nanjing, 210029, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Hong
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, 300 Guangzhou Road, Nanjing, 210029, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, 300 Guangzhou Road, Nanjing, 210029, China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, 300 Guangzhou Road, Nanjing, 210029, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, 300 Guangzhou Road, Nanjing, 210029, China.
authors.forename: Jiayu
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, 300 Guangzhou Road, Nanjing, 210029, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Lian
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, 300 Guangzhou Road, Nanjing, 210029, China.
authors.forename: Yanru
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, 300 Guangzhou Road, Nanjing, 210029, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, 300 Guangzhou Road, Nanjing, 210029, China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Mao
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, 300 Guangzhou Road, Nanjing, 210029, China. Yaoyu.chen@njmu.edu.cn.
authors.forename: Yaoyu
authors.identifier: 0000-0002-1245-1146
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D003847:Deoxyglucose / Q000494:pharmacology; D005260:Female; D055785:Gene Knockdown Techniques; D006019:Glycolysis / Q000187:drug effects; D064593:Heterografts; D006801:Humans; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis / Q000235:genetics / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D025481:Phosphofructokinase-2 / Q000502:physiology; D010744:Phosphoric Monoester Hydrolases; D010879:Piperazines; D011379:Prognosis; D034741:RNA, Small Interfering / Q000138:chemical synthesis / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D051017:Apoptosis Regulatory Proteins; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D010879:Piperazines; D034741:RNA, Small Interfering; C482205:nutlin 3; D003847:Deoxyglucose; C107345:PFKFB3 protein, human; D025481:Phosphofructokinase-2; D010744:Phosphoric Monoester Hydrolases; C512708:TIGAR protein, human
keywords: Acute myeloid leukemia; Apoptosis; Glycolysis; Survival; TIGAR