title: Tauroursodeoxycholate inhibits human cholangiocarcinoma growth via Ca2+-, PKC-, and MAPK-dependent pathways.
abstract: Tauroursodeoxychate (TUDCA) is used for the treatment of cholangiopathies including primary sclerosing cholangitis, which is considered the primary risk factor for cholangiocarcinoma. The effect of TUDCA on cholangiocarcinoma growth is unknown. We evaluated the role of TUDCA in the regulation of growth of the cholangiocarcinoma cell line Mz-ChA-1. TUDCA inhibited the growth of Mz-ChA-1 cells in concentration- and time-dependent manners. TUDCA inhibition of cholangiocarcinoma growth was blocked by BAPTA-AM, an intracellular Ca(2+) concentration ([Ca(2+)](i)) chelator, and H7, a PKC-alpha inhibitor. TUDCA increased [Ca(2+)](i) and membrane translocation of the Ca(2+)-dependent PKC-alpha in Mz-ChA-1 cells. TUDCA inhibited the activity of MAPK, and this inhibitory effect of TUDCA was abrogated by BAPTA-AM and H7. TUDCA did not alter the activity of Raf-1 and B-Raf and the phosphorylation of MAPK p38 and JNK/stress-activated protein kinase. TUDCA inhibits Mz-ChA-1 growth through a signal-transduction pathway involving MAPK p42/44 and PKC-alpha but independent from Raf proteins and MAPK p38 and JNK/stress-activated protein kinases. TUDCA may be important for the treatment of cholangiocarcinoma.
authors.affiliation: Department of Internal Medicine, Scott & White Hospital and The Texas A & M University System Health Science Center, College of Medicine, and Central Texas Veterans Health Care System, Temple, USA.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Alpini
authors.forename: Noriatsu
authors.initials: N
authors.lastname: Kanno
authors.forename: Jo Lynne
authors.initials: JL
authors.lastname: Phinizy
authors.forename: Shannon
authors.initials: S
authors.lastname: Glaser
authors.forename: Heather
authors.initials: H
authors.lastname: Francis
authors.forename: Silvia
authors.initials: S
authors.lastname: Taffetani
authors.forename: Gene
authors.initials: G
authors.lastname: LeSage
mesh_terms: D001650:Bile Duct Neoplasms / Q000378:metabolism* / Q000473:pathology*; D001653:Bile Ducts, Intrahepatic; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009994:Osmolar Concentration; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D051571:Protein Kinase C-alpha; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D013655:Taurochenodeoxycholic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; C496628:PRKCA protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium