title: The effect of acyclic retinoid on the metabolomic profiles of hepatocytes and hepatocellular carcinoma cells.
abstract: OBJECTIVE
  Acyclic retinoid (ACR) is a promising chemopreventive agent for hepatocellular carcinoma (HCC) that selectively inhibits the growth of HCC cells (JHH7) but not normal hepatic cells (Hc). To better understand the molecular basis of the selective anti-cancer effect of ACR, we performed nuclear magnetic resonance (NMR)-based and capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS)-based metabolome analyses in JHH7 and Hc cells after treatment with ACR.
  
  
  RESULTS
  NMR-based metabolomics revealed a distinct metabolomic profile of JHH7 cells at 18 h after ACR treatment but not at 4 h after ACR treatment. CE-TOFMS analysis identified 88 principal metabolites in JHH7 and Hc cells after 24 h of treatment with ethanol (EtOH) or ACR. The abundance of 71 of these metabolites was significantly different between EtOH-treated control JHH7 and Hc cells, and 49 of these metabolites were significantly down-regulated in the ACR-treated JHH7 cells compared to the EtOH-treated JHH7 cells. Of particular interest, the increase in adenosine-5'-triphosphate (ATP), the main cellular energy source, that was observed in the EtOH-treated control JHH7 cells was almost completely suppressed in the ACR-treated JHH7 cells; treatment with ACR restored ATP to the basal levels observed in both EtOH-control and ACR-treated Hc cells (0.72-fold compared to the EtOH control-treated JHH7 cells). Moreover, real-time PCR analyses revealed that ACR significantly increased the expression of pyruvate dehydrogenase kinases 4 (PDK4), a key regulator of ATP production, in JHH7 cells but not in Hc cells (3.06-fold and 1.20-fold compared to the EtOH control, respectively).
  
  
  CONCLUSIONS
  The results of the present study suggest that ACR may suppress the enhanced energy metabolism of JHH7 cells but not Hc cells; this occurs at least in part via the cancer-selective enhancement of PDK4 expression. The cancer-selective metabolic pathways identified in this study will be important targets of the anti-cancer activity of ACR.
authors.affiliation: Micro-signaling Regulation Technology Unit, RIKEN Center for Life Science Technologies, Wako, Saitama, Japan ; Japan Society for the Promotion of Science, Tokyo, Japan.
authors.forename: Xian-Yang
authors.initials: XY
authors.lastname: Qin
authors.affiliation: Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo, Japan ; Japan Society for the Promotion of Science, Tokyo, Japan.
authors.forename: Feifei
authors.initials: F
authors.lastname: Wei
authors.affiliation: Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Tanokura
authors.affiliation: Tokyo New Drug Research Laboratories, Pharmaceutical Division, KOWA Company, Ltd., Tokyo, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Ishibashi
authors.affiliation: Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Shimizu
authors.affiliation: Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Hisataka
authors.initials: H
authors.lastname: Moriwaki
authors.affiliation: Micro-signaling Regulation Technology Unit, RIKEN Center for Life Science Technologies, Wako, Saitama, Japan.
authors.forename: Soichi
authors.initials: S
authors.lastname: Kojima
mesh_terms: D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019075:Electrophoresis, Capillary / Q000379:methods; D004734:Energy Metabolism / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D055442:Metabolome / Q000187:drug effects*; D009928:Organ Specificity; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D016588:Anticarcinogenic Agents; C000631432:PDK4 protein, human; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D014212:Tretinoin; C034534:3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases