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

(2015) ONCOTARGET. 6(29). p.28011-28025
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Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
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.
Keywords
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

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Citation

Please use this url to cite or link to this publication:

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, Yves-Paul, 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.
@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},
}

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