Upregulation of the NADPH oxidase NOX4 by TGF-beta in hepatocytes is required for its pro-apoptotic activity

Carmona-Cuenca, Irene; Roncero, César; Sancho, Patricia; Caja, Laia; Fausto, Nelson; Fernández, Margarita; Fabregat, Isabel

doi:10.1016/j.jhep.2008.07.021

Cited by 201 publications

(185 citation statements)

References 47 publications

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“…To exert its proapoptotic activity in hepatocytes, TGF-␤ requires the production of reactive oxygen species (13,14), mainly originated by the NADPH oxidase NOX4, which is necessary for apoptosis execution in hepatocytes sensitive to the cytokine (15). However, the role of NADPH oxidases in TGF-␤-mediated signaling in liver is complex.…”

Section: Mary Our Results Suggest That Ptp1b Deficiency Confers Resimentioning

confidence: 99%

Protein-tyrosine Phosphatase 1B (PTP1B) Deficiency Confers Resistance to Transforming Growth Factor-β (TGF-β)-induced Suppressor Effects in Hepatocytes

Ortiz

Caja

Bertrán

et al. 2012

Journal of Biological Chemistry

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Background: Tyrosine kinases and phosphatases modulate TGF-␤ signaling. Results: PTP1B deficiency attenuates TGF-␤-induced Smad phosphorylation correlating with suppression of growth inhibition and apoptosis, an effect that is reverted by genistein, and p65 or NOX1 knockdown. Conclusion: Lack of PTP1B impairs Smad activation in a NOX1 and NF-B-dependent manner. Significance: New insights are opened into the role of phosphatases in TGF-␤ signaling.

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Section: Mary Our Results Suggest That Ptp1b Deficiency Confers Resimentioning

confidence: 99%

Protein-tyrosine Phosphatase 1B (PTP1B) Deficiency Confers Resistance to Transforming Growth Factor-β (TGF-β)-induced Suppressor Effects in Hepatocytes

Ortiz

Caja

Bertrán

et al. 2012

Journal of Biological Chemistry

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“…NOX4 is a key mediator of TGF-b action in hepatocytes. 47 TGF-b production is elevated in steatotic livers triggering fibrosis through upregulation of a-SMA production by activated hepatic stellate cells. 36 In line with these data, NOX4-deficient mice failed to upregulate a-SMA expression in response to HFD feeding.…”

Section: Discussionmentioning

confidence: 99%

Deficiency in the NADPH oxidase 4 predisposes towards diet-induced obesity

Mouche

Sajic

et al. 2012

Int J Obes

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OBJECTIVE: NADPH oxidase 4 (NOX4) is a reactive oxygen species (ROS) producing NADPH oxidase that regulates redox homeostasis in diverse insulin-sensitive cell types. In particular, NOX4-derived ROS is a key modulator of adipocyte differentiation and mediates insulin receptor signaling in mature adipocytes in vitro. Our study was aimed at investigating the role of NOX4 in adipose tissue differentiation, whole body metabolic homeostasis and insulin sensitivity in vivo. DESIGN: Mice with genetic ablation of NOX4 (NOX4-deficient mice) were subjected to chow or high-fat-containing diet for 12 weeks. Body weight gain, adiposity, insulin sensitivity, and adipose tissue and liver gene and protein expression were analyzed and compared with similarly treated wild-type mice. RESULTS: Here, we report that NOX4-deficient mice display latent adipose tissue accumulation and are susceptible to diet-induced obesity and early onset insulin resistance. Obesity results from accelerated adipocyte differentiation and hypertrophy, and an increase in whole body energy efficiency. Insulin resistance is associated with increased adipose tissue hypoxia, inflammation and adipocyte apoptosis. In the liver, more severe diet-induced steatosis was observed due to the lack of proper upregulation of mitochondrial fatty acid b-oxidation. CONCLUSION: These findings identify NOX4 as a regulator of metabolic homeostasis. Moreover, they indicate an anti-adipogenic role for NOX4 in vivo and reveal its function as a protector against the development of diet-induced obesity, insulin resistance and hepatosteatosis.

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“…In the liver, the isoforms NOX1, NOX2 and NOX4 are expressed by fetal and adult hepatocytes ( [5], Fig. 1C), although they might have opposite effects controlling cell death: NOX4 favoring apoptosis whilst NOX1 favors survival [6,8].…”

Section: Discussionmentioning

confidence: 99%

“…In fact, we have previously described that fetal rat hepatocytes show Nox1, Nox2, and Nox4 expression in basal conditions [5] showing apparent opposite roles in the control of liver cell death. Thus, NOX4 is necessary for the triggering of apoptosis induced by a physiological stimulus, such as the Transforming Growth Factor-beta (TGF-) [6] or antineoplastic drugs, such as doxorubicin [7]. On the contrary, NOX1 might be involved in protecting cells from TGF- proapoptotic signals in both fetal hepatocytes and hepatoma cells [5,8].…”

Section: Introductionmentioning

confidence: 99%

The NADPH oxidase inhibitor VAS2870 impairs cell growth and enhances TGF-β-induced apoptosis of liver tumor cells

Sancho

Fabregat

2011

Biochemical Pharmacology

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This compound inhibits dose-dependently autocrine increase of cell number in FaO rat hepatoma cells, and almost completely blocked ROS production and thymidine incorporation when used at 25 M. Such inhibitory effect on autocrine growth is coincident with lower mRNA levels of EGFR (Epidermal Growth Factor Receptor) and its ligand TGF-(Transforming Growth Factor-alpha), and decreased phosphorylation of the EGFR itself and other downstream targets, such as SRC or AKT. Moreover, NADPH oxidase pharmacological inhibition also effectively attenuates serum-dependent growth and phosphorylation of AKT and ERK. Importantly, these inhibitory effects on either autocrine or serum-dependent cell growth are observed in several human HCC cell lines. Finally, we have observed that VAS2870 is also effective in enhancing apoptosis induced by a physiological stimulus, such as TGF-. In summary, NADPH oxidase pharmacological inhibition could be considered a promising tool in the treatment of liver cancer.

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Upregulation of the NADPH oxidase NOX4 by TGF-beta in hepatocytes is required for its pro-apoptotic activity

Cited by 201 publications

References 47 publications

Protein-tyrosine Phosphatase 1B (PTP1B) Deficiency Confers Resistance to Transforming Growth Factor-β (TGF-β)-induced Suppressor Effects in Hepatocytes

Protein-tyrosine Phosphatase 1B (PTP1B) Deficiency Confers Resistance to Transforming Growth Factor-β (TGF-β)-induced Suppressor Effects in Hepatocytes

Deficiency in the NADPH oxidase 4 predisposes towards diet-induced obesity

The NADPH oxidase inhibitor VAS2870 impairs cell growth and enhances TGF-β-induced apoptosis of liver tumor cells

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