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: Yves-Paul Vandewynckel, Debby Laukens, Lindsey Devisscher, Annelies Paridaens, Eliene Bogaerts, Xavier Verhelst, Anja Van den Bussche, Sarah Raevens, Christophe Van Steenkiste, Marleen Van Troys, Christophe Ampe, Benedicte Descamps, Chris Vanhove, Olivier Govaere, Anja Geerts, Hans Van Vlierberghe
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 29 Pg. 28011-25 (Sep 29 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26293671 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Carcinogens
• Taurochenodeoxycholic Acid
• ursodoxicoltaurine

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Carcinogens (toxicity)
• Carcinoma, Hepatocellular (pathology)
• Disease Models, Animal
• Endoplasmic Reticulum Stress (drug effects)
• Hep G2 Cells
• Humans
• Immunohistochemistry
• In Situ Nick-End Labeling
• Liver Neoplasms (pathology)
• Male
• Mice
• Real-Time Polymerase Chain Reaction
• Taurochenodeoxycholic Acid (pharmacology)
• Xenograft Model Antitumor Assays