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.

Bavachin Induces Apoptosis through Mitochondrial Regulated ER Stress Pathway in HepG2 Cells

“…It is reported that TUDCA reduces ER stress through binding to the hydrophobic regions of proteins, and promoting the protein folding and aggregation. 44,45) This result indicated that bavachin-induced apoptosis was associated with ER stress pathways.…”

Up‐regulation of golgi α‐mannosidase IA and down‐regulation of golgi α‐mannosidase IC activates unfolded protein response during hepatocarcinogenesis

“…UPR is an important tightly regulated response required for cellular homeostasis, and it intersects with many other pathways that are critical for glucose metabolism, glycogen synthesis, lipid metabolism, inflammation, and metabolic disease 45. Recent studies have shown that the UPR plays a role in liver disease,46, 47 that its activation is associated with hepatic insulin resistance and fatty acid flux,48, 49 and that the UPR mediator XBP1 can up‐regulate hepatic lipogenic factor 47, 50. Our study suggests that overexpression of MAN1A1 leads to steatosis, inflammation, and HCC formation, possibly through the UPR, perhaps evoking the transcriptional networks involved in hepatocarcinogenesis.…”

Combination of tauroursodeoxycholic acid and N‐acetylcysteine exceeds standard treatment for acetaminophen intoxication

“…In this context, we are interested in tauroursodeoxycholic acid (TUDCA), a safe hydrophilic bile acid that is known for its ER stress-reducing capacities in hepatic and non-hepatic cells in vitro and in vivo. [20][21][22][23][24][25][26][27][28][29][30][31][32] TUDCA has recently been shown to bind to the hydrophobic regions of proteins, acting as a chemical chaperone, preventing subsequent protein aggregation and unfolded protein accumulation, thus diminishing ER stress. 33 In this study, we investigated the mode of cell death and UPR activation following experimental APAP overdose in mice and whether modulating these processes by TUDCA might provide an additional therapeutic effect to the standard of care treatment with NAC.…”