title: Sodium taurocholate cotransporting polypeptide mediates dual actions of deoxycholic acid in human hepatocellular carcinoma cells: enhanced apoptosis versus growth stimulation.
abstract: OBJECTIVE
  The hydrophobic bile acid, deoxycholic acid (DC), can induce apoptosis in hepatocytes. The roles of DC and its transporter are not yet established in hepatocellular carcinoma (HCC) cells. We investigated DC-induced alterations in HCC cell growth, with a particular focus on the effect of the expression of bile acid (BA)-transporting Na(+)-dependent taurocholic cotransporting polypeptides (NTCPs).
  
  
  METHODS
  We determined NTCP expression in four human HCC cell lines: Huh-BAT, Huh-7, SNU-761, and SNU-475. NTCP expression and apoptotic signaling cascades were examined by immunoblot analyses. Cell viability was assessed using the 3,4-(5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt assay. Wound healing and invasion assays were performed to evaluate cell migration and invasion abilities. Real-time polymerase chain reaction was performed to measure IL-8 expression levels. Nuclear factor kappa B (NF-κB) activity was evaluated by enzyme-linked immunosorbent assay.
  
  
  RESULTS
  The HCC cell lines revealed varying NTCP expression levels, and DC treatment had dual effects, depending on NTCP expression. DC induced apoptosis in NTCP-positive HCC cells, especially under hypoxic conditions. In NTCP-negative HCC cells, simultaneous treatment with DC and cyclooxygenase inhibitor markedly decreased aggressive cellular behaviors via the inhibition of NF-κB/COX-2/IL-8 pathways.
  
  
  CONCLUSIONS
  Hydrophobic bile acid offers therapeutic potential for patients with advanced HCC via different mechanisms depending on NTCP expression levels within the tumor.
authors.affiliation: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul National University Hospital, 101 Daehakro, Chongno-gu, Seoul, 110-744, Republic of Korea.
authors.forename: Eun Sun
authors.initials: ES
authors.lastname: Jang
authors.forename: Jung-Hwan
authors.initials: JH
authors.lastname: Yoon
authors.forename: Sung-Hee
authors.initials: SH
authors.lastname: Lee
authors.forename: Soo-Mi
authors.initials: SM
authors.lastname: Lee
authors.forename: Jeong-Hoon
authors.initials: JH
authors.lastname: Lee
authors.forename: Su Jong
authors.initials: SJ
authors.lastname: Yu
authors.forename: Yoon Jun
authors.initials: YJ
authors.lastname: Kim
authors.forename: Hyo-Suk
authors.initials: HS
authors.lastname: Lee
authors.forename: Chung Yong
authors.initials: CY
authors.lastname: Kim
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D003840:Deoxycholic Acid / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology; D004790:Enzyme Induction / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D029363:Organic Anion Transporters, Sodium-Dependent / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism; D027981:Symporters / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: C473772:GPBAR1 protein, human; D016209:Interleukin-8; D016328:NF-kappa B; D029363:Organic Anion Transporters, Sodium-Dependent; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D027981:Symporters; D003840:Deoxycholic Acid; C071908:sodium-bile acid cotransporter; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D066246:ErbB Receptors