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Tauroursodeoxycholic acid dampens oncogenic apoptosis induced by endoplasmic reticulum stress during hepatocarcinogen exposure
- Source :
- ONCOTARGET, Oncotarget
- Publication Year :
- 2015
-
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.
- Subjects :
- Male
Programmed cell death
Carcinoma, Hepatocellular
LIVER
Blotting, Western
Taurochenodeoxycholic acid
Antineoplastic Agents
Apoptosis
Tumor initiation
KAPPA-B
Biology
Real-Time Polymerase Chain Reaction
Taurochenodeoxycholic Acid
ACTIVATION
chemistry.chemical_compound
Mice
RETINAL DEGENERATION
In Situ Nick-End Labeling
Medicine and Health Sciences
Animals
Humans
chemoprevention
chaperone
UNFOLDED PROTEIN RESPONSE
Endoplasmic reticulum
Liver Neoplasms
CARCINOGENESIS
HUMAN HEPATOCELLULAR-CARCINOMA
Tauroursodeoxycholic acid
Hep G2 Cells
unfolded protein response
hepatocellular carcinoma
Endoplasmic Reticulum Stress
Immunohistochemistry
Xenograft Model Antitumor Assays
IκBα
Disease Models, Animal
Oncology
chemistry
CELL-DEATH
Tumor progression
inflammation
AUTOPHAGIC FLUX
Immunology
Unfolded protein response
Cancer research
Carcinogens
BILE
Research Paper
Subjects
Details
- Language :
- English
- ISSN :
- 19492553
- Database :
- OpenAIRE
- Journal :
- ONCOTARGET, Oncotarget
- Accession number :
- edsair.doi.dedup.....26de9628d555424f32d8d378b4f82358