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

Yves-Paul Vandewynckel, Debby Laukens UGent, Lindsey Devisscher UGent, Annelies Paridaens, Eliene Bogaerts, Xavier Verhelst UGent, Anja Van den Bussche, Sarah Raevens UGent, Christophe Van Steenkiste UGent, Marleen Van Troys UGent, et al. (2015) ONCOTARGET. 6(29). p.28011-28025
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-kappa B inhibitor I kappa 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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
unfolded protein response, hepatocellular carcinoma, inflammation, chemoprevention, chaperone, HUMAN HEPATOCELLULAR-CARCINOMA, UNFOLDED PROTEIN RESPONSE, RETINAL DEGENERATION, AUTOPHAGIC FLUX, CELL-DEATH, KAPPA-B, LIVER, BILE, ACTIVATION, CARCINOGENESIS
journal title
ONCOTARGET
Oncotarget
volume
6
issue
29
pages
28011 - 28025
Web of Science type
Article
Web of Science id
000363161300116
JCR category
ONCOLOGY
JCR impact factor
5.008 (2015)
JCR rank
36/213 (2015)
JCR quartile
1 (2015)
ISSN
1949-2553
DOI
10.18632/oncotarget.4377
project
Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
language
English
UGent publication?
yes
classification
A1
copyright statement
I have retained and own the full copyright for this publication
id
6913451
handle
http://hdl.handle.net/1854/LU-6913451
date created
2015-08-24 15:21:54
date last changed
2017-02-22 13:52:56
@article{6913451,
  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-kappa B inhibitor I kappa 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.},
  author       = {Vandewynckel, Yves-Paul and Laukens, Debby and Devisscher, Lindsey and Paridaens, Annelies and Bogaerts, Eliene and Verhelst, Xavier and Van den Bussche, Anja and Raevens, Sarah and Van Steenkiste, Christophe and Van Troys, Marleen and Ampe, Christophe and Descamps, Benedicte and Vanhove, Christian and Govaere, Olivier  and Geerts, Anja and Van Vlierberghe, Hans},
  issn         = {1949-2553},
  journal      = {ONCOTARGET},
  keyword      = {unfolded protein response,hepatocellular carcinoma,inflammation,chemoprevention,chaperone,HUMAN HEPATOCELLULAR-CARCINOMA,UNFOLDED PROTEIN RESPONSE,RETINAL DEGENERATION,AUTOPHAGIC FLUX,CELL-DEATH,KAPPA-B,LIVER,BILE,ACTIVATION,CARCINOGENESIS},
  language     = {eng},
  number       = {29},
  pages        = {28011--28025},
  title        = {Tauroursodeoxycholic acid dampens oncogenic apoptosis induced by endoplasmic reticulum stress during hepatocarcinogen exposure},
  url          = {http://dx.doi.org/10.18632/oncotarget.4377},
  volume       = {6},
  year         = {2015},
}

Chicago
Vandewynckel, Yves-Paul, Debby Laukens, Lindsey Devisscher, Annelies Paridaens, Eliene Bogaerts, Xavier Verhelst, Anja Van den Bussche, et al. 2015. “Tauroursodeoxycholic Acid Dampens Oncogenic Apoptosis Induced by Endoplasmic Reticulum Stress During Hepatocarcinogen Exposure.” Oncotarget 6 (29): 28011–28025.
APA
Vandewynckel, Y.-P., Laukens, D., Devisscher, L., Paridaens, A., Bogaerts, E., Verhelst, X., Van den Bussche, A., et al. (2015). Tauroursodeoxycholic acid dampens oncogenic apoptosis induced by endoplasmic reticulum stress during hepatocarcinogen exposure. ONCOTARGET, 6(29), 28011–28025.
Vancouver
1.
Vandewynckel Y-P, Laukens D, Devisscher L, Paridaens A, Bogaerts E, Verhelst X, et al. Tauroursodeoxycholic acid dampens oncogenic apoptosis induced by endoplasmic reticulum stress during hepatocarcinogen exposure. ONCOTARGET. 2015;6(29):28011–25.
MLA
Vandewynckel, Yves-Paul, Debby Laukens, Lindsey Devisscher, et al. “Tauroursodeoxycholic Acid Dampens Oncogenic Apoptosis Induced by Endoplasmic Reticulum Stress During Hepatocarcinogen Exposure.” ONCOTARGET 6.29 (2015): 28011–28025. Print.