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Tauroursodeoxycholic acid dampens oncogenic apoptosis induced by endoplasmic reticulum stress during hepatocarcinogen exposure

Lookup NU author(s): Dr Olivier Govaere

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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 2a (eIf2a) 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-?B inhibitor I?Ba. 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.


Publication metadata

Author(s): Vandewyncke Y-P, Laukens D, Devisscher L, Paridaens A, Bogaerts E, Verhelst X, Van den Bussche A, Raevens S, Van Govaere C, Van Troys M, Ampe C, Descamps B, Vanhove C, Govaere O, Geerts A, Van Vlierberghe H

Publication type: Article

Publication status: Published

Journal: Oncotarget

Year: 2015

Volume: 6

Issue: 29

Pages: 28011-28025

Online publication date: 20/07/2015

Acceptance date: 10/07/2015

ISSN (electronic): 1949-2553

Publisher: Impact Journals LLC

URL: https://doi.org/10.18632/oncotarget.4377

DOI: 10.18632/oncotarget.4377

PubMed id: 26293671


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