Activation of the Metallothionein IIA Promoter and Other Key Stress Response Elements by Ursodeoxycholate in HepG2 Cells: Relevance to the Cytoprotective Function of Ursodeoxycholate

Bernstein, Carol; Payne, Claire M.; Bernstein, Harris; Garewal, Harinder S.

doi:10.1159/000056179

Cited by 24 publications

(11 citation statements)

References 36 publications

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“…Reduction in ATF4 in cells treated with TUDCA for longer duration (Fig. 6A) may be due to the antioxidant activity associated with TUDCA which can increase thiol containing proteins, scavenge hydroxyl radicals and can also activate metallothionein promoters in hepatocytes and in HepG2 cells 15, 52 . Enhanced levels of eIF2α phosphorylation observed in cells treated with TUDCA and in UV-irradiation compared to tunicamycin may be a consequence of little or no expression of CHOP that in turn targets the expression of GADD-34, a cofactor of eIF2α phosphatase (Figs 5 and 6).…”

Section: Discussionmentioning

confidence: 99%

Chemical chaperone, TUDCA unlike PBA, mitigates protein aggregation efficiently and resists ER and non-ER stress induced HepG2 cell death

Uppala

Gani

Konakanchi

2017

Sci Rep

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Stress induced BSA (bovine serum albumin) protein aggregation is effectively mitigated in vitro by TUDCA (tauroursodeoxycholic acid) than by PBA (4- phenylbutyric acid), chemical chaperones approved by FDA for the treatment of biliary cirrhosis and urea cycle disorders respectively. TUDCA, unlike PBA, enhances trypsin mediated digestion of BSA. TUDCA activates PERK, an ER-resident kinase that phosphorylates the alpha-subunit of eukaryotic initiation factor2 (eIF2α) and promotes the expression of activated transcription factor 4 (ATF4) in HepG2 cells. In contrast, PBA induced eIF2α phosphorylation is not mediated by PERK activation and results in low ATF4 expression. Neither chaperones promote expression of BiP, an ER chaperone, and CHOP (C/EBP homologous protein), downstream target of eIF2α-ATF4 pathway. Both chaperones mitigate tunicamycin induced PERK-eIF2α-ATF4-CHOP arm of UPR and expression of BiP. TUDCA, unlike PBA does not decrease cell viability and it also mitigates tunicamycin, UV-irradiation and PBA induced PARP (poly ADP-ribose polymerase) cleavage and cell death. These findings therefore suggest that TUDCA’s antiapoptotic activity to protect HepG2 cells and PBA’s activity that limits tumor cell progression may be important while considering their therapeutic potential.

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Section: Discussionmentioning

confidence: 99%

Chemical chaperone, TUDCA unlike PBA, mitigates protein aggregation efficiently and resists ER and non-ER stress induced HepG2 cell death

Uppala

Gani

Konakanchi

2017

Sci Rep

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“…UDCA could inhibit tumour development in azoxymethane and dextran-related colitis models by counteracting the tumour-promoting effects of secondary bile acids such as DCA (Earnest et al, 1994;Wali et al, 1995;Loddenkemper et al, 2006). In high-risk patients, retrospective and prospective studies have suggested a beneficial effect of UDCA on colonic carcinogenesis (Kowdley, 2000;Tung et al, 2001;Bernstein et al, 2002;Pardi et al, 2003;Serfaty et al, 2003;Goldman et al, 2010). UDCA supplementation was associated with a nonstatistically significant reduction in total colorectal adenoma recurrence, but with a statistically significant 39% reduction in recurrence of adenomas with high-grade dysplasia (Alberts et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Opposing effects of bile acids deoxycholic acid and ursodeoxycholic acid on signal transduction pathways in oesophageal cancer cells

Abdel-Latif

Inoue

Reynolds

2016

European Journal of Cancer Prevention

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Ursodeoxycholic acid (UDCA) was reported to reduce bile acid toxicity, but the mechanisms underlying its cytoprotective effects are not fully understood. The aim of the present study was to examine the effects of UDCA on the modulation of deoxycholic acid (DCA)-induced signal transduction in oesophageal cancer cells. Nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) activity was assessed using a gel shift assay. NF-κB activation and translocation was performed using an ELISA-based assay and immunofluorescence analysis. COX-2 expression was analysed by western blotting and COX-2 promoter activity was assessed by luciferase assay. DCA induced NF-κB and AP-1 DNA-binding activities in SKGT-4 and OE33 cells. UDCA pretreatment inhibited DCA-induced NF-κB and AP-1 activation and NF-κB translocation. This inhibitory effect was coupled with a blockade of IκB-α degradation and inhibition of phosphorylation of IKK-α/β and ERK1/2. Moreover, UDCA pretreatment inhibited COX-2 upregulation. Using transient transfection of the COX-2 promoter, UDCA pretreatment abrogated DCA-induced COX-2 promoter activation. In addition, UDCA protected oesophageal cells from the apoptotic effects of deoxycholate. Our findings indicate that UDCA inhibits DCA-induced signalling pathways in oesophageal cancer cells. These data indicate a possible mechanistic role for the chemopreventive actions of UDCA in oesophageal carcinogenesis.

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“…Whether CNT2 plays a role in the response of hepatocytes to apoptosis, either favouring it or acting as a survival signal, is currently under investigation. Nevertheless, it is interesting to note that bile acids have been shown to have a dual role in the programmed cell death of hepatocytes, since hydrophobic (DCA and GCDCA) and hydrophilic (TCA and UDCA) bile acids have been considered to promote apoptosis and to up-regulate selected survival mechanisms respectively [39][40][41]. Moreover, hydrophilic anions such as UDCA and TUDCA are known to be cytoprotective against oxidative stress [42] and to suppress mitochondrial membrane perturbation [43].…”

Section: Discussionmentioning

confidence: 99%

Bile acids alter the subcellular localization of CNT2 (concentrative nucleoside cotransporter) and increase CNT2-related transport activity in liver parenchymal cells

Fernández-Veledo¹,

Huber-Ruano²,

Aymerich³

et al. 2014

Biochemical Journal

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CNT2 (concentrative nucleoside cotransporter) is a plasma membrane high-affinity Na + -coupled adenosine transporter, also localized in intracellular structures. This transporter protein may play additional roles other than nucleoside salvage, since it has recently been shown to be under purinergic control via K ATP channels, by a mechanism that does not seem to involve changes in its subcellular localization. In an attempt to identify the agents that promote CNT2 trafficking, bile acids were found to increase CNT2-related transport activity in a K ATP channel-independent manner in both Fao hepatoma and rat liver parenchymal cells. A maximum effect was recorded after treatment with hydrophilic anions such as TCA (taurocholate). However, this effect did not involve changes in the amount of CNT2 protein, it was instead associated with a subcellular redistribution of CNT2, resulting in an accumulation of the transporter at the plasma membrane. This was deduced from subcellular fractionation studies, biotinylation of plasma membrane proteins and subsequent CNT2 detection in streptavidin precipitates and in vivo confocal microscopic analysis of the distribution of a YFP (yellow fluorescent protein)-CNT2 construct. The induction of CNT2 translocation, triggered by TCA, was inhibited by wortmannin, dibutyryl-AMPc, PD98059 and colchicine, thus suggesting the involvement of the PI3K/ERK (phosphoinositide 3-kinase/extracellular-signal related kinase) pathway in microtubule-dependent activation of recombinant CNT2. These are novel effects of bile-acid physiology and provide the first evidence for short-term regulation of CNT2 translocation into and from the plasma membrane.

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Activation of the Metallothionein IIA Promoter and Other Key Stress Response Elements by Ursodeoxycholate in HepG2 Cells: Relevance to the Cytoprotective Function of Ursodeoxycholate

Cited by 24 publications

References 36 publications

Chemical chaperone, TUDCA unlike PBA, mitigates protein aggregation efficiently and resists ER and non-ER stress induced HepG2 cell death

Chemical chaperone, TUDCA unlike PBA, mitigates protein aggregation efficiently and resists ER and non-ER stress induced HepG2 cell death

Opposing effects of bile acids deoxycholic acid and ursodeoxycholic acid on signal transduction pathways in oesophageal cancer cells

Bile acids alter the subcellular localization of CNT2 (concentrative nucleoside cotransporter) and increase CNT2-related transport activity in liver parenchymal cells

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