GCDCA down-regulates gene expression by increasing Sp1 binding to the NOS-3 promoter in an oxidative stress dependent manner

González-Rubio, Sandra; López‐Sánchez, Laura M.; Muñoz‐Castañeda, Juan R.; Linares, Clara I.; Aguilar-Melero, Patricia; Rodríguez‐Perálvarez, Manuel; Sánchez‐Sánchez, Rafael; Fernández-Alvarez, Ana Julia; Casado, Marta; Montero-Álvarez, José Luis; Rodríguez‐Ariza, Antonio; Muntané, Jordi; Mata, Manuel de la; Ferrín, Gustavo

doi:10.1016/j.bcp.2015.04.017

Cited by 14 publications

(22 citation statements)

References 52 publications

(67 reference statements)

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“…In the liver, chronic cholestasis is a risk factor for HCC development and conversely advanced HCC usually provokes a progressive cholestatic effect. Glycochenodeoxycholic acid, which is a glycine-conjugated form of the primary bile acid chenodeoxycholic acid, is highly cytotoxic in a dose-dependent manner and its exposure in cellular models of the disease [49] activates cellular autophagy through the AMPK/mTOR pathway to promote HCC invasiveness [50]. Secondary biliary acids produced by the metabolic activity of the gut microbiota are also able to enhance AKT-independent mTOR activity in the liver to promote hepatic steatosis and HCC, while depleting gut microbiota with antibiotics reverses these mechanisms [51].…”

Section: Regulation Of the Mtor Pathway In Liver Diseases And Hccmentioning

confidence: 99%

Activation of mTOR Signaling Pathway in Hepatocellular Carcinoma

Ferrín

Guerrero

Amado

et al. 2020

IJMS

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Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and occurs mainly in patients with liver cirrhosis. The mammalian target of rapamycin (mTOR) signaling pathway is involved in many hallmarks of cancer including cell growth, metabolism re-programming, proliferation and inhibition of apoptosis. The mTOR pathway is upregulated in HCC tissue samples as compared with the surrounding liver cirrhotic tissue. In addition, the activation of mTOR is more intense in the tumor edge, thus reinforcing its role in HCC proliferation and spreading. The inhibition of the mTOR pathway by currently available pharmacological compounds (i.e., sirolimus or everolimus) is able to hamper tumor progression both in vitro and in animal models. The use of mTOR inhibitors alone or in combination with other therapies is a very attractive approach, which has been extensively investigated in humans. However, results are contradictory and there is no solid evidence suggesting a true benefit in clinical practice. As a result, neither sirolimus nor everolimus are currently approved to treat HCC or to prevent tumor recurrence after curative surgery. In the present comprehensive review, we analyzed the most recent scientific evidence while providing some insights to understand the gap between experimental and clinical studies.

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Section: Regulation Of the Mtor Pathway In Liver Diseases And Hccmentioning

confidence: 99%

Activation of mTOR Signaling Pathway in Hepatocellular Carcinoma

Ferrín

Guerrero

Amado

et al. 2020

IJMS

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“…SP1 is essential for cell growth and differentiation 34 . In particular in neurons, SP1 DNA-binding complex is induced by oxidative stress, especially as early response to cell stress 35 . We can suppose that in consequence of oxidative stress, YY1 gives an early response binding DNA and inducing looser conformation of chromatin; this helps the connections of CREB and SP1.…”

Section: Discussionmentioning

confidence: 99%

Characterization of human mitochondrial ferritin promoter: identification of transcription factors and evidences of epigenetic control

Guaraldo

Santambrogio

Rovelli

et al. 2016

Sci Rep

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Mitochondrial ferritin (FtMt) is an iron storage protein belonging to the ferritin family but, unlike the cytosolic ferritin, it has an iron-unrelated restricted tissue expression. FtMt appears to be preferentially expressed in cell types characterized by high metabolic activity and oxygen consumption, suggesting a role in protecting mitochondria from iron-dependent oxidative damage. The human gene (FTMT) is intronless and its promoter region has not been described yet. To analyze the regulatory mechanisms controlling FTMT expression, we characterized the 5′ flanking region upstream the transcriptional starting site of FTMT by in silico enquiry of sequences conservation, DNA deletion analysis, and ChIP assay. The data revealed a minimal promoter region and identified the presence of SP1, CREB and YY1 as positive regulators, and GATA2, FoxA1 and C/EBPβ as inhibitors of the transcriptional regulation. Furthermore, the FTMT transcription is increased by acetylating and de-methylating agent treatments in K562 and HeLa cells. These treatments up-regulate FtMt expression even in fibroblasts derived from a Friedreich ataxia patient, where it might exert a beneficial effect against mitochondrial oxidative damage. The expression of FTMT appears regulated by a complex mechanism involving epigenetic events and interplay between transcription factors.

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“…GCDA is a conjugated bile acid, which has been reported to promote oxidative stress in hepatic cells. 20 DNA damage was observed following the alkaline comet assay (Figure 1(a) and (b)). In contrast, we did not observe much DNA damage when the neutral comet assay was used (Figure 1(c) and (d)).…”

Section: Gcda Induced Ap-site Production In Hepatic Cellsmentioning

confidence: 99%

Mcl-1 suppresses abasic site repair following bile acid–induced hepatic cellular DNA damage

Zhang

Liu

et al. 2017

Tumour Biol.

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In cholestasis, increases in bile acid levels result in the generation of reactive oxygen species and the induction of DNA damage and mutation. It is believed that bile acid accumulation is associated with liver tumorigenesis. However, the mechanism that underpins this phenomenon remains to be elucidated. Mcl-1, which is overexpressed in hepatic cells, is a pro-survival member of the Bcl-2 family. In this study, we observed that Mcl-1 potently suppresses the repair of bile acid-induced abasic (apurinic/apyrimidinic) sites in DNA lesions. Upon exposure of hepatic cells to glycochenodeoxycholate, one of the major conjugated human bile acids, we observed an increase in AP site accumulation along with induction of poly(ADP-ribose) polymerase and XRCC1 ( X-Ray Repair Cross Complementing 1). In addition, accumulation of Mcl-1 was observed in the nuclei of QGY-7703 cells in response to glycochenodeoxycholate stimulation. Knockdown of endogenous Mcl-1 by RNA interference significantly accelerated the repair of DNA lesions in glycochenodeoxycholate-treated cells. However, unlike XRCC1, poly(ADP-ribose) polymerase was induced following Mcl-1 knockdown. Conversely, poly(ADP-ribose) polymerase suppression was observed following glycochenodeoxycholate treatment of cells overexpressing Mcl-1. Moreover, AP-site counting analyses revealed that DNA repair activity was enhanced in cells overexpressing poly(ADP-ribose) polymerase under glycochenodeoxycholate stress conditions. It is well known that poly(ADP-ribose) polymerase plays a crucial role in the base excision repair pathway. Thus, our findings suggest that Mcl-1 suppresses base excision repair by inhibiting poly(ADP-ribose) polymerase induction following glycochenodeoxycholate-induced DNA damage. These results potentially explain how bile acid accumulation results in genetic instability and carcinogenesis.

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GCDCA down-regulates gene expression by increasing Sp1 binding to the NOS-3 promoter in an oxidative stress dependent manner

Cited by 14 publications

References 52 publications

Activation of mTOR Signaling Pathway in Hepatocellular Carcinoma

Activation of mTOR Signaling Pathway in Hepatocellular Carcinoma

Characterization of human mitochondrial ferritin promoter: identification of transcription factors and evidences of epigenetic control

Mcl-1 suppresses abasic site repair following bile acid–induced hepatic cellular DNA damage

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