title: Tauroursodeoxycholic acid dampens oncogenic apoptosis induced by endoplasmic reticulum stress during hepatocarcinogen exposure.
abstract: Hepatocellular carcinoma (HCC) is characterized by the accumulation of unfolded proteins in the endoplasmic reticulum (ER), which activates the unfolded protein response (UPR). However, the role of ER stress in tumor initiation and progression is controversial. To determine the impact of ER stress, we applied tauroursodeoxycholic acid (TUDCA), a bile acid with chaperone properties. The effects of TUDCA were assessed using a diethylnitrosamine-induced mouse HCC model in preventive and therapeutic settings. Cell metabolic activity, proliferation and invasion were investigated in vitro. Tumor progression was assessed in the HepG2 xenograft model. Administration of TUDCA in the preventive setting reduced carcinogen-induced elevation of alanine and aspartate aminotransferase levels, apoptosis of hepatocytes and tumor burden. TUDCA also reduced eukaryotic initiation factor 2α (eIf2α) phosphorylation, C/EBP homologous protein expression and caspase-12 processing. Thus, TUDCA suppresses carcinogen-induced pro-apoptotic UPR. TUDCA alleviated hepatic inflammation by increasing NF-κB inhibitor IκBα. Furthermore, TUDCA altered the invasive phenotype and enhanced metabolic activity but not proliferation in HCC cells. TUDCA administration after tumor development did not alter orthotopic tumor or xenograft growth. Taken together, TUDCA attenuates hepatocarcinogenesis by suppressing carcinogen-induced ER stress-mediated cell death and inflammation without stimulating tumor progression. Therefore, this chemical chaperone could represent a novel chemopreventive agent.
authors: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors: Yves-Paul
authors: YP
authors: Vandewynckel
authors: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors: Debby
authors: D
authors: Laukens
authors: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors: Lindsey
authors: L
authors: Devisscher
authors: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors: Annelies
authors: A
authors: Paridaens
authors: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors: Eliene
authors: E
authors: Bogaerts
authors: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors: Xavier
authors: X
authors: Verhelst
authors: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors: Anja
authors: A
authors: Van den Bussche
authors: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors: Sarah
authors: S
authors: Raevens
authors: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors: Christophe
authors: C
authors: Van Steenkiste
authors: Department of Biochemistry, Ghent University, Ghent, Belgium.
authors: Marleen
authors: M
authors: Van Troys
authors: Department of Biochemistry, Ghent University, Ghent, Belgium.
authors: Christophe
authors: C
authors: Ampe
authors: Infinity Imaging Laboratory, Ghent University, Ghent, Belgium.
authors: Benedicte
authors: B
authors: Descamps
authors: Infinity Imaging Laboratory, Ghent University, Ghent, Belgium.|GROUP-ID Consortium, Ghent University, Ghent, Belgium.
authors: Chris
authors: C
authors: Vanhove
authors: Translational Cell and Tissue Research, Department of Imaging and Pathology, University of Leuven, Leuven, Belgium.
authors: Olivier
authors: O
authors: Govaere
authors: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors: Anja
authors: A
authors: Geerts
authors: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors: Hans
authors: H
authors: Van Vlierberghe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008113:Liver Neoplasms / Q000473:pathology*; D008297:Male; D051379:Mice; D060888:Real-Time Polymerase Chain Reaction; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002273:Carcinogens; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine
keywords: chaperone; chemoprevention; hepatocellular carcinoma; inflammation; unfolded protein response