title: Retinoic acid-related orphan receptor alpha reprograms glucose metabolism in glutamine-deficient hepatoma cells.
abstract: The metabolism of glutamine and glucose is recognized as a promising therapeutic target for the treatment of cancer; however, targeted molecules that mediate glutamine and glucose metabolism in cancer cells have not been addressed. Here, we show that restricting the supply of glutamine in hepatoma cells, including HepG2 and Hep3B cells, markedly increased the expression of retinoic acid-related orphan receptor alpha (RORα). Up-regulation of RORα in glutamine-deficient hepatoma cells resulted from an increase in the level of cellular reactive oxygen species and in the nicotinamide adenine dinucleotide phosphate/nicotinamide adenine dinucleotide phosphate reduced (NADP+ /NADPH) ratio, which was consistent with a reduction in the glutathione/glutathione disulfide (GSH/GSSG) ratio. Adenovirus (Ad)-mediated overexpression of RORα (Ad-RORα) or treatment with the RORα activator, SR1078, reduced aerobic glycolysis and down-regulated biosynthetic pathways in hepatoma cells. Ad-RORα and SR1078 reduced the expression of pyruvate dehydrogenase kinase 2 (PDK2) and inhibited the phosphorylation of pyruvate dehydrogenase and subsequently shifted pyruvate to complete oxidation. The RORα-mediated decrease in PDK2 levels was caused by up-regulation of p21, rather than p53. Furthermore, RORα inhibited hepatoma growth both in vitro and in a xenograft model in vivo. We also found that suppression of PDK2 inhibited hepatoma growth in a xenograft model. These findings mimic the altered glucose utilization and hepatoma growth caused by glutamine deprivation. Finally, tumor tissue from 187 hepatocellular carcinoma patients expressed lower levels of RORα than adjacent nontumor tissue, supporting a potential beneficial effect of RORα activation in the treatment of liver cancer.
  
  
  CONCLUSIONS
  RORα mediates reprogramming of glucose metabolism in hepatoma cells in response to glutamine deficiency. The relationships established here between glutamine metabolism, RORα expression and signaling, and aerobic glycolysis have implications for therapeutic targeting of liver cancer metabolism.
authors.affiliation: Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, South Korea.
authors.forename: Jun-Kyu
authors.initials: JK
authors.lastname: Byun
authors.forename: Yeon-Kyung
authors.initials: YK
authors.lastname: Choi
authors.forename: Yu Na
authors.initials: YN
authors.lastname: Kang
authors.forename: Byoung Kuk
authors.initials: BK
authors.lastname: Jang
authors.forename: Koo Jeong
authors.initials: KJ
authors.lastname: Kang
authors.forename: Yong Hyun
authors.initials: YH
authors.lastname: Jeon
authors.forename: Ho-Won
authors.initials: HW
authors.lastname: Lee
authors.forename: Jae-Han
authors.initials: JH
authors.lastname: Jeon
authors.forename: Seung-Hoi
authors.initials: SH
authors.lastname: Koo
authors.forename: Won-Il
authors.initials: WI
authors.lastname: Jeong
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harris
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
authors.forename: Keun-Gyu
authors.initials: KG
authors.lastname: Park
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology; D005260:Female; D005947:Glucose / Q000378:metabolism*; D005973:Glutamine / Q000172:deficiency*; D006019:Glycolysis; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; C000631430:PDK2 protein, human; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; C539738:RORA protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D005973:Glutamine; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; D005947:Glucose