title: FLIP(L) is critical for aerobic glycolysis in hepatocellular carcinoma.
abstract: BACKGROUND
  Tumor cells use aerobic glycolysis to rapidly generate ATP and growth substrate which expenses a large amount of glucose. However, how tumor cells take in enough glucose from the tumor microenvironment of insufficient blood supply remains poorly understood. The cellular FLICE-like inhibitory protein (FLIP), a cell apoptosis inhibiting molecule, is highly expressed in hepatocellular carcinoma (HCC) and is implicated in HCC development.
  
  
  METHODS
  The effects of FLIPL (the long form of FLIP) on aerobic glycolysis and glucose uptake were assessed in HCC cells and xenograft tumors. The correlations between FLIPL expression and sodium/glucose cotransporter 1 (SGLT1) expression in clinical HCC tissues were analyzed. The consequences of FLIPL-induced regulation of SGLT1 at the transcription and translation levels and the interaction between FLIPL and SGLT1 were examined. FLIPL-mediated tolerance upon glucose limitation and its mechanism were detected.
  
  
  RESULTS
  We report a novel role for FLIPL in promoting the aerobic glycolysis of HCC cells. FLIPL overexpression induced a significant increase in cell aerobic glycolysis indexes including glucose uptake, glucose consumption, and lactate production. FLIPL co-localized and interacted with SGLT1, a major active glucose transporter in HCC cells. FLIPL increased the stability of SGLT1 protein by inhibiting its ubiquitination and degradation. The expression level of FLIPL was positively correlated with the expression level of SGLT1 in 79 HCC tissues from surgical operation. Furthermore, FLIPL increased cell tolerance ability and decreased cell apoptosis to low glucose by regulating SGLT1.
  
  
  CONCLUSIONS
  Our results indicate that FLIPL plays an essential role in HCC aerobic glycolysis and that SGLT1 is required for FLIPL-modulated tumor proliferation under low glucose conditions. Targeting the actions of FLIPL in cell glucose-dependent aerobic glycolysis may provide an attractive strategy for therapeutic intervention in HCC.
authors.affiliation: Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, 1 Xinsi Road, Xi'an, 710032, Shaanxi, China.|Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, 169 Changle West Road, Xi'an, Shaanxi, 710032, China.
authors.forename: Shixiong
authors.initials: S
authors.lastname: Lei
authors.affiliation: Department of General Surgery, 210 Hospital of Chinese People's Liberation Army, Dalian, 116021, China.
authors.forename: Jiandong
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, 1 Xinsi Road, Xi'an, 710032, Shaanxi, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, 169 Changle West Road, Xi'an, Shaanxi, 710032, China.
authors.forename: Jiachen
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, 169 Changle West Road, Xi'an, Shaanxi, 710032, China.
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, 1 Xinsi Road, Xi'an, 710032, Shaanxi, China.
authors.forename: Haili
authors.initials: H
authors.lastname: Tang
authors.affiliation: Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, 1 Xinsi Road, Xi'an, 710032, Shaanxi, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, 1 Xinsi Road, Xi'an, 710032, Shaanxi, China.
authors.forename: An
authors.initials: A
authors.lastname: Chen
authors.affiliation: Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, 1 Xinsi Road, Xi'an, 710032, Shaanxi, China.
authors.forename: Huadong
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, 169 Changle West Road, Xi'an, Shaanxi, 710032, China. liyann@fmmu.edu.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, 1 Xinsi Road, Xi'an, 710032, Shaanxi, China. duxl0705@fmmu.edu.cn.
authors.forename: Xilin
authors.initials: X
authors.lastname: Du
mesh_terms: D000818:Animals; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009368:Neoplasm Transplantation; D051269:Sodium-Glucose Transporter 1 / Q000235:genetics* / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; C495674:SLC5A1 protein, human; D051269:Sodium-Glucose Transporter 1
keywords: Aerobic glycolysis; Cellular FLICE-like inhibitory protein; Glucose uptake; Hepatocellular carcinoma; Sodium-glucose cotransporter 1