Tauroursodeoxycholic acid dampens oncogenic apoptosis induced by endoplasmic reticulum stress during hepatocarcinogen exposure
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Yves-Paul Vandewynckel1, Debby Laukens1, Lindsey Devisscher1, Annelies Paridaens1, Eliene Bogaerts1, Xavier Verhelst1, Anja Van den Bussche1, Sarah Raevens1, Christophe Van Steenkiste1, Marleen Van Troys2, Christophe Ampe2, Benedicte Descamps3, Chris Vanhove3,4, Olivier Govaere5, Anja Geerts1, Hans Van Vlierberghe1
1Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium
2Department of Biochemistry, Ghent University, Ghent, Belgium
3Infinity Imaging Lab, Ghent University, Ghent, Belgium
4GROUP-ID Consortium, Ghent University, Ghent, Belgium
5Translational Cell and Tissue Research, Department of Imaging and Pathology, University of Leuven, Leuven, Belgium
Hans Van Vlierberghe, e-mail: Hans.VanVlierberghe@UGent.be
Keywords: hepatocellular carcinoma, unfolded protein response, inflammation, chemoprevention, chaperone
Received: January 22, 2015 Accepted: July 10, 2015 Published: July 20, 2015
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.
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