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Elias S J Arner - One of the best experts on this subject based on the ideXlab platform.
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selenoprotein gene nomenclature
Journal of Biological Chemistry, 2016Co-Authors: Brigelius Flohe Regina, Vadim N Gladyshev, Elias S J Arner, Marla J Berry, Elspeth A Bruford, Raymond F Burk, Bradley A Carlson, Sergi Castellano, Laurent ChavatteAbstract:Abstract The human genome contains 25 genes coding for selenocysteine-containing proteins (selenoproteins). These proteins are involved in a variety of functions, most notably redox homeostasis. Selenoprotein enzymes with known functions are designated according to these functions: TXNRD1, TXNRD2, and TXNRD3 (thioredoxin reductases), GPX1, GPX2, GPX3, GPX4 and GPX6 (glutathione peroxidases), DIO1, DIO2, and DIO3 (iodothyronine deiodinases), MSRB1 (methionine-R-sulfoxide reductase 1) and SEPHS2 (selenophosphate synthetase 2). Selenoproteins without known functions have traditionally been denoted by SEL or SEP symbols. However, these symbols are sometimes ambiguous and conflict with the approved nomenclature for several other genes. Therefore, there is a need to implement a rational and coherent nomenclature system for selenoprotein-encoding genes. Our solution is to use the root symbol SELENO followed by a letter. This nomenclature applies to SELENOF (selenoprotein F, the 15 kDa selenoprotein, SEP15), SELENOH (selenoprotein H, SELH, C11orf31), SELENOI (selenoprotein I, SELI, EPT1), SELENOK (selenoprotein K, SELK), SELENOM (selenoprotein M, SELM), SELENON (selenoprotein N, SEPN1, SELN), SELENOO (selenoprotein O, SELO), SELENOP (selenoprotein P, SeP, SEPP1, SELP), SELENOS (selenoprotein S, SELS, SEPS1, VIMP), SELENOT (selenoprotein T, SELT), SELENOV (selenoprotein V, SELV) and SELENOW (selenoprotein W, SELW, SEPW1). This system, approved by the HUGO Gene Nomenclature Committee, also resolves conflicting, missing and ambiguous designations for selenoprotein genes and is applicable to selenoproteins across vertebrates.
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Thioredoxin reductase 1 suppresses adipocyte differentiation and insulin responsiveness
Scientific Reports, 2016Co-Authors: Xiaoxiao Peng, Marcus Conrad, Alfredo Giménez-cassina, Paul Petrus, Mikael Rydén, Elias S J ArnerAbstract:Recently thioredoxin reductase 1 (TrxR1), encoded by TXNRD1, was suggested to modulate glucose and lipid metabolism in mice. Here we discovered that TrxR1 suppresses insulin responsiveness, anabolic metabolism and adipocyte differentiation. Immortalized mouse embryonic fibroblasts (MEFs) lacking TXNRD1 (TXNRD1−/−) displayed increased metabolic flux, glycogen storage, lipogenesis and adipogenesis. This phenotype coincided with upregulated PPARγ expression, promotion of mitotic clonal expansion and downregulation of p27 and p53. Enhanced Akt activation also contributed to augmented adipogenesis and insulin sensitivity. Knockdown of TXNRD1 transcripts accelerated adipocyte differentiation also in human primary preadipocytes. Furthermore, TXNRD1 transcript levels in subcutaneous adipose tissue from 56 women were inversely associated with insulin sensitivity in vivo and lipogenesis in their isolated adipocytes. These results suggest that TrxR1 suppresses anabolic metabolism and adipogenesis by inhibition of intracellular signaling pathways downstream of insulin stimulation.
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Sec-containing TrxR1 is essential for self-sufficiency of cells by control of glucose-derived H2O2.
Cell Death and Disease, 2014Co-Authors: Xiaoxiao Peng, Marcus Conrad, Pankaj Mandal, Vitaliy O. Kaminskyy, Arne Lindqvist, Elias S J ArnerAbstract:It is commonly recognized that diabetic complications involve increased oxidative stress directly triggered by hyperglycemia. The most important cellular protective systems against such oxidative stress have yet remained unclear. Here we show that the selenoprotein thioredoxin reductase 1 (TrxR1), encoded by the TXNRD1 gene, is an essential enzyme for such protection. Individually grown TXNRD1 knockout (TXNRD1−/−) mouse embryonic fibroblasts (MEFs) underwent massive cell death directly linked to glucose-induced H2O2 production. This death and excessive H2O2 levels could be reverted by reconstituted expression of selenocysteine (Sec)-containing TrxR1, but not by expression of Sec-devoid variants of the enzyme. Our results show that Sec-containing TrxR1 is absolutely required for self-sufficient growth of MEFs under high-glucose conditions, owing to an essential importance of this enzyme for elimination of glucose-derived H2O2. To our knowledge, this is the first time a strict Sec-dependent function of TrxR1 has been identified as being essential for mammalian cells.
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A TXNRD1-dependent metabolic switch alters hepatic lipogenesis, glycogen storage, and detoxification
Free Radical Biology and Medicine, 2013Co-Authors: Sonya V. Iverson, Mario R. Capecchi, Justin R. Prigge, Elias S J Arner, Sofi Eriksson, Tesia A. Meade, Emily A. Talago, Erin S. Meade, Edward E. SchmidtAbstract:Besides helping to maintain a reducing intracellular environment, the thioredoxin (Trx) system impacts bioenergetics and drug metabolism. We show that hepatocyte-specific disruption of TXNRD1, encoding Trx reductase-1 (TrxR1), causes a metabolic switch in which lipogenic genes are repressed and periportal hepatocytes become engorged with glycogen. These livers also overexpress machinery for biosynthesis of glutathione and conversion of glycogen into UDP-glucuronate; they stockpile glutathione-S-transferases and UDP-glucuronyl-transferases; and they overexpress xenobiotic exporters. This realigned metabolic profile suggested that the mutant hepatocytes might be preconditioned to more effectively detoxify certain xenobiotic challenges. Hepatocytes convert the pro-toxin acetaminophen (APAP, paracetamol) into cytotoxic N-acetyl-p-benzoquinone imine (NAPQI). APAP defenses include glucuronidation of APAP or glutathionylation of NAPQI, allowing removal by xenobiotic exporters. We found that NAPQI directly inactivates TrxR1, yet TXNRD1-null livers were resistant to APAP-induced hepatotoxicity. TXNRD1-null livers did not have more effective gene expression responses to APAP challenge; however, their constitutive metabolic state supported more robust GSH biosynthesis, glutathionylation, and glucuronidation systems. Following APAP challenge, this effectively sustained the GSH system and attenuated damage.
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The rare TXNRD1_v3 ("v3") splice variant of human thioredoxin reductase 1 protein is targeted to membrane rafts by N-acylation and induces filopodia independently of its redox active site integrity.
Journal of Biological Chemistry, 2013Co-Authors: Marcus Cebula, Naazneen Moolla, Alexio Capovilla, Elias S J ArnerAbstract:Abstract The human selenoprotein thioredoxin reductase 1 (TrxR1), encoded by the TXNRD1 gene, is a key player in redox regulation. Alternative splicing generates several TrxR1 variants, one of which is v3 that carries an atypical N-terminal glutaredoxin domain. When overexpressed, v3 associates with membranes and triggers formation of filopodia. Here we found that membrane targeting of v3 is mediated by myristoylation and palmitoylation of its N-terminal MGC-motif, through which v3 specifically targets membrane rafts. This was suggested by its localization in cholera toxin subunit B-stained membrane areas and also shown using lipid fractionation experiments. Utilizing site-directed mutant variants we also found that v3-mediated generation of filopodia is independent of the Cys residues in its redox active site, but dependent upon its membrane raft targeting. These results identify v3 as an intricately regulated protein that expands TXNRD1-derived protein functions to the membrane raft compartment.
Vincent L. Cryns - One of the best experts on this subject based on the ideXlab platform.
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Lysine oxidase exposes a dependency on the thioredoxin antioxidant pathway in triple-negative breast cancer cells
Breast Cancer Research and Treatment, 2020Co-Authors: Olga E. Chepikova, Dmitry Malin, Elena Strekalova, Elena V. Lukasheva, Andrey A. Zamyatnin, Vincent L. CrynsAbstract:Purpose Transformed cells are vulnerable to depletion of certain amino acids. Lysine oxidase (LO) catalyzes the oxidative deamination of lysine, resulting in lysine depletion and hydrogen peroxide production. Although LO has broad antitumor activity in preclinical models, the cytotoxic mechanisms of LO are poorly understood. Methods Triple (ER/PR/HER2)-negative breast cancer (TNBC) cells were treated with control media, lysine-free media or control media supplemented with LO and examined for cell viability, caspase activation, induction of reactive oxygen species (ROS) and antioxidant signaling. To determine the role of nuclear factor erythroid 2-related factor 2 (NRF2) and thioredoxin reductase-1 (TXNRD1) in LO-induced cell death, NRF2 and TXNRD1 were individually silenced by RNAi. Additionally, the pan-TXNRD inhibitor auranofin was used in combination with LO. Results LO activates caspase-independent cell death that is suppressed by necroptosis and ferroptosis inhibitors, which are inactive against lysine depletion, pointing to fundamental differences between LO and lysine depletion. LO rapidly induces ROS with a return to baseline levels within 24 h that coincides temporally with induction of TXNRD activity, the rate-limiting enzyme in the thioredoxin antioxidant pathway. ROS induction is required for LO-mediated cell death and NRF2-dependent induction of TXNRD1. Silencing NRF2 or TXNRD1 enhances the cytotoxicity of LO. The pan-TXNRD inhibitor auranofin is synergistic with LO against transformed breast epithelial cells, but not untransformed cells, underscoring the tumor-selectivity of this strategy. Conclusions LO exposes a redox vulnerability of TNBC cells to TXNRD inhibition by rendering tumor cells dependent on the thioredoxin antioxidant pathway for survival.
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Lysine oxidase exposes a dependency on the thioredoxin antioxidant pathway in triple-negative breast cancer cells
Breast Cancer Research and Treatment, 2020Co-Authors: Olga E. Chepikova, Dmitry Malin, Elena Strekalova, Elena V. Lukasheva, Andrey A. Zamyatnin, Vincent L. CrynsAbstract:Transformed cells are vulnerable to depletion of certain amino acids. Lysine oxidase (LO) catalyzes the oxidative deamination of lysine, resulting in lysine depletion and hydrogen peroxide production. Although LO has broad antitumor activity in preclinical models, the cytotoxic mechanisms of LO are poorly understood. Triple (ER/PR/HER2)-negative breast cancer (TNBC) cells were treated with control media, lysine-free media or control media supplemented with LO and examined for cell viability, caspase activation, induction of reactive oxygen species (ROS) and antioxidant signaling. To determine the role of nuclear factor erythroid 2-related factor 2 (NRF2) and thioredoxin reductase-1 (TXNRD1) in LO-induced cell death, NRF2 and TXNRD1 were individually silenced by RNAi. Additionally, the pan-TXNRD inhibitor auranofin was used in combination with LO. LO activates caspase-independent cell death that is suppressed by necroptosis and ferroptosis inhibitors, which are inactive against lysine depletion, pointing to fundamental differences between LO and lysine depletion. LO rapidly induces ROS with a return to baseline levels within 24 h that coincides temporally with induction of TXNRD activity, the rate-limiting enzyme in the thioredoxin antioxidant pathway. ROS induction is required for LO-mediated cell death and NRF2-dependent induction of TXNRD1. Silencing NRF2 or TXNRD1 enhances the cytotoxicity of LO. The pan-TXNRD inhibitor auranofin is synergistic with LO against transformed breast epithelial cells, but not untransformed cells, underscoring the tumor-selectivity of this strategy. LO exposes a redox vulnerability of TNBC cells to TXNRD inhibition by rendering tumor cells dependent on the thioredoxin antioxidant pathway for survival.
Masanobu Kitagawa - One of the best experts on this subject based on the ideXlab platform.
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SECISBP2 is a novel prognostic predictor that regulates selenoproteins in diffuse large B-cell lymphoma
Laboratory Investigation, 2020Co-Authors: Towako Taguchi, Morito Kurata, Iichiroh Onishi, Yuko Kinowako, Yunosuke Sato, Sayuri Shiono, Sachiko Ishibashi, Masumi Ikeda, Masahide Yamamoto, Masanobu KitagawaAbstract:The overexpression of glutathione peroxidase 4 (GPX4; an enzyme that suppresses peroxidation of membrane phospholipids) is considered a poor prognostic predictor of diffuse large B-cell lymphoma (DLBCL). However, the mechanisms employed in GPX4 overexpression remain unknown. GPX4 is translated as a complete protein upon the binding of SECISBP2 to the selenocysteine insertion sequence (SECIS) on the 3′UTR of GPX4 mRNA. In this study, we investigated the expression of SECISBP2 and its subsequent regulation of GPX4 and TXNRD1 in DLBCL patients. Moreover, we determined the significance of the expression of these selenoproteins in vitro using MD901 and Raji cells. SECISBP2 was positive in 45.5% (75/165 cases) of DLBCL samples. The SECISBP2-positive group was associated with low overall survival (OS) as compared to the SECISBP2-negative group ( P = 0.006). Similarly, the SECISBP2 and GPX4 or TXNRD1 double-positive groups ( P
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SECISBP2 is a novel prognostic predictor that regulates selenoproteins in diffuse large B-cell lymphoma
Laboratory Investigation, 2020Co-Authors: Towako Taguchi, Morito Kurata, Iichiroh Onishi, Yuko Kinowako, Yunosuke Sato, Sayuri Shiono, Sachiko Ishibashi, Masumi Ikeda, Masahide Yamamoto, Masanobu KitagawaAbstract:SECISBP2 overexpression is an independent negative prognostic predictor in diffuse large B-cell lymphoma. Additionally, SECISBP2 positively correlates with selenoprotein expression. In vitro, SECISBP2 knockout increases intracellular reactive oxygen species accumulation via the downregulation of selenoproteins, inhibiting cell growth and promoting cell death after doxorubicin treatment. Therefore, SECISBP2 is a potential therapeutic target for malignant lymphoma. The overexpression of glutathione peroxidase 4 (GPX4; an enzyme that suppresses peroxidation of membrane phospholipids) is considered a poor prognostic predictor of diffuse large B-cell lymphoma (DLBCL). However, the mechanisms employed in GPX4 overexpression remain unknown. GPX4 is translated as a complete protein upon the binding of SECISBP2 to the selenocysteine insertion sequence (SECIS) on the 3′UTR of GPX4 mRNA. In this study, we investigated the expression of SECISBP2 and its subsequent regulation of GPX4 and TXNRD1 in DLBCL patients. Moreover, we determined the significance of the expression of these selenoproteins in vitro using MD901 and Raji cells. SECISBP2 was positive in 45.5% (75/165 cases) of DLBCL samples. The SECISBP2-positive group was associated with low overall survival (OS) as compared to the SECISBP2-negative group ( P = 0.006). Similarly, the SECISBP2 and GPX4 or TXNRD1 double-positive groups ( P
Olga E. Chepikova - One of the best experts on this subject based on the ideXlab platform.
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Lysine oxidase exposes a dependency on the thioredoxin antioxidant pathway in triple-negative breast cancer cells
Breast Cancer Research and Treatment, 2020Co-Authors: Olga E. Chepikova, Dmitry Malin, Elena Strekalova, Elena V. Lukasheva, Andrey A. Zamyatnin, Vincent L. CrynsAbstract:Purpose Transformed cells are vulnerable to depletion of certain amino acids. Lysine oxidase (LO) catalyzes the oxidative deamination of lysine, resulting in lysine depletion and hydrogen peroxide production. Although LO has broad antitumor activity in preclinical models, the cytotoxic mechanisms of LO are poorly understood. Methods Triple (ER/PR/HER2)-negative breast cancer (TNBC) cells were treated with control media, lysine-free media or control media supplemented with LO and examined for cell viability, caspase activation, induction of reactive oxygen species (ROS) and antioxidant signaling. To determine the role of nuclear factor erythroid 2-related factor 2 (NRF2) and thioredoxin reductase-1 (TXNRD1) in LO-induced cell death, NRF2 and TXNRD1 were individually silenced by RNAi. Additionally, the pan-TXNRD inhibitor auranofin was used in combination with LO. Results LO activates caspase-independent cell death that is suppressed by necroptosis and ferroptosis inhibitors, which are inactive against lysine depletion, pointing to fundamental differences between LO and lysine depletion. LO rapidly induces ROS with a return to baseline levels within 24 h that coincides temporally with induction of TXNRD activity, the rate-limiting enzyme in the thioredoxin antioxidant pathway. ROS induction is required for LO-mediated cell death and NRF2-dependent induction of TXNRD1. Silencing NRF2 or TXNRD1 enhances the cytotoxicity of LO. The pan-TXNRD inhibitor auranofin is synergistic with LO against transformed breast epithelial cells, but not untransformed cells, underscoring the tumor-selectivity of this strategy. Conclusions LO exposes a redox vulnerability of TNBC cells to TXNRD inhibition by rendering tumor cells dependent on the thioredoxin antioxidant pathway for survival.
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Lysine oxidase exposes a dependency on the thioredoxin antioxidant pathway in triple-negative breast cancer cells
Breast Cancer Research and Treatment, 2020Co-Authors: Olga E. Chepikova, Dmitry Malin, Elena Strekalova, Elena V. Lukasheva, Andrey A. Zamyatnin, Vincent L. CrynsAbstract:Transformed cells are vulnerable to depletion of certain amino acids. Lysine oxidase (LO) catalyzes the oxidative deamination of lysine, resulting in lysine depletion and hydrogen peroxide production. Although LO has broad antitumor activity in preclinical models, the cytotoxic mechanisms of LO are poorly understood. Triple (ER/PR/HER2)-negative breast cancer (TNBC) cells were treated with control media, lysine-free media or control media supplemented with LO and examined for cell viability, caspase activation, induction of reactive oxygen species (ROS) and antioxidant signaling. To determine the role of nuclear factor erythroid 2-related factor 2 (NRF2) and thioredoxin reductase-1 (TXNRD1) in LO-induced cell death, NRF2 and TXNRD1 were individually silenced by RNAi. Additionally, the pan-TXNRD inhibitor auranofin was used in combination with LO. LO activates caspase-independent cell death that is suppressed by necroptosis and ferroptosis inhibitors, which are inactive against lysine depletion, pointing to fundamental differences between LO and lysine depletion. LO rapidly induces ROS with a return to baseline levels within 24 h that coincides temporally with induction of TXNRD activity, the rate-limiting enzyme in the thioredoxin antioxidant pathway. ROS induction is required for LO-mediated cell death and NRF2-dependent induction of TXNRD1. Silencing NRF2 or TXNRD1 enhances the cytotoxicity of LO. The pan-TXNRD inhibitor auranofin is synergistic with LO against transformed breast epithelial cells, but not untransformed cells, underscoring the tumor-selectivity of this strategy. LO exposes a redox vulnerability of TNBC cells to TXNRD inhibition by rendering tumor cells dependent on the thioredoxin antioxidant pathway for survival.
Qingzhu Gao - One of the best experts on this subject based on the ideXlab platform.
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slc27a5 deficiency activates nrf2 TXNRD1 pathway by increased lipid peroxidation in hcc
Cell Death & Differentiation, 2020Co-Authors: Qingzhu Gao, Guiji Zhang, Yaqiu Zheng, Yi Yang, Chang Chen, Jie Xia, Li Liang, Chong Lei, Xuefei Cai, Wenlu ZhangAbstract:Solute carrier family 27 member 5 (SLC27A5/FATP5) is involved in fatty acid transport and bile acid metabolism; however, little is known about its role in human diseases. Here, we first show that SLC27A5 expression is downregulated in hepatocellular carcinoma (HCC) by DNA hypermethylation, and reduced SCL27A5 expression contributes to tumor progression and poor prognosis. Both gain- and loss-of-function studies demonstrated that SLC27A5 has an antiproliferative effect on HCC cells in vitro and in vivo. Knockout of SLC27A5 increases polyunsaturated lipids, leading to increased NADP+/NADPH ratio, ROS production as well as lipid peroxidation and the subsequent accumulation of 4-hydroxy-2-nonenal (4-HNE) in hepatoma cells. Mass spectrometry analysis found that 4-HNE directly modifies cysteine residues (Cys513, 518) on KEAP1, thus leading KEAP1/NRF2 pathway activation and increases the expression levels of NRF2 target genes, such as TXNRD1. Further, SLC27A5 expression negatively correlates with TXNRD1 expression in hepatoma cells and clinical HCC samples, and blockade of NRF2/TXNRD1 using genetic approaches or inhibitors sensitizes SLC27A5-deficient hepatoma cells to sorafenib treatment. Collectively, we demonstrated that SLC27A5 acts as a novel tumor suppressor by suppressing TXNRD1 expression via the KEAP1/NRF2 pathway in HCC. Combination therapy of sorafenib and NRF2/TXNRD1 inhibitors may be a promising strategy in personalized HCC treatment.
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SLC27A5 deficiency activates NRF2/TXNRD1 pathway by increased lipid peroxidation in HCC.
Cell Death & Differentiation, 2019Co-Authors: Qingzhu Gao, Guiji Zhang, Yaqiu Zheng, Yi Yang, Chang Chen, Jie Xia, Li Liang, Chong Lei, Xuefei CaiAbstract:Solute carrier family 27 member 5 (SLC27A5/FATP5) is involved in fatty acid transport and bile acid metabolism; however, little is known about its role in human diseases. Here, we first show that SLC27A5 expression is downregulated in hepatocellular carcinoma (HCC) by DNA hypermethylation, and reduced SCL27A5 expression contributes to tumor progression and poor prognosis. Both gain- and loss-of-function studies demonstrated that SLC27A5 has an antiproliferative effect on HCC cells in vitro and in vivo. Knockout of SLC27A5 increases polyunsaturated lipids, leading to increased NADP+/NADPH ratio, ROS production as well as lipid peroxidation and the subsequent accumulation of 4-hydroxy-2-nonenal (4-HNE) in hepatoma cells. Mass spectrometry analysis found that 4-HNE directly modifies cysteine residues (Cys513, 518) on KEAP1, thus leading KEAP1/NRF2 pathway activation and increases the expression levels of NRF2 target genes, such as TXNRD1. Further, SLC27A5 expression negatively correlates with TXNRD1 expression in hepatoma cells and clinical HCC samples, and blockade of NRF2/TXNRD1 using genetic approaches or inhibitors sensitizes SLC27A5-deficient hepatoma cells to sorafenib treatment. Collectively, we demonstrated that SLC27A5 acts as a novel tumor suppressor by suppressing TXNRD1 expression via the KEAP1/NRF2 pathway in HCC. Combination therapy of sorafenib and NRF2/TXNRD1 inhibitors may be a promising strategy in personalized HCC treatment.
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PCK1 Downregulation Promotes TXNRD1 Expression and Hepatoma Cell Growth via the Nrf2/Keap1 Pathway.
Frontiers in Oncology, 2018Co-Authors: Lin Tuo, Qingzhu Gao, Guiji Zhang, Yi Yang, Jie Xia, Li Liang, Jin Xiang, Xuanming Pan, Kai Wang, Ni TangAbstract:Gluconeogenesis, generates glucose from small carbohydrate substrates, and drives the metabolic flux in parallel but opposite to glycolysis. The cytoplasmic isoform of phosphoenolpyruvate carboxykinase (PCK1 or PEPCK-C), a rate-limiting enzyme in gluconeogenesis, initiates the gluconeogenesis process and is reportedly dysregulated in multiple types of cancer. Gluconeogenesis mainly occurs in the liver during fasting, and previous studies have demonstrated that PCK1 acts as a tumor suppressor in hepatocellular carcinoma (HCC); however, the role of PCK1 in cancer progression remains incompletely understood. In the current study, we found that PCK1 expression was decreased in HCC as compared to adjacent normal liver tissues, and low PCK1 expression correlated with poor patient prognosis. Furthermore, overexpression of PCK1 suppressed reactive oxygen species (ROS) production and nuclear translocation of Nrf2 in hepatoma cells. In addition, thioredoxin reductase 1 (TXNRD1), an antioxidant enzyme regulated by the Nrf2/Keap1 pathway, was downregulated upon overexpression of PCK1 in HCC cell lines. Furthermore, we verified this axis using nude mouse xenograft model. Finally, we found that auranofin, a TXNRD1 inhibitor, enhanced the sensitivity of PCK1-knockout hepatoma cells to sorafenib-induced apoptosis. Taken together, our findings suggest that PCK1 deficiency promotes hepatoma cell proliferation via the induction of oxidative stress and the activation of transcription factor Nrf2, and that targeting the TXNRD1 antioxidant pathway sensitizes PCK1-knockout hepatoma cells to sorafenib treatment in vitro.
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pck1 downregulation promotes TXNRD1 expression and hepatoma cell growth via the nrf2 keap1 pathway
Frontiers in Oncology, 2018Co-Authors: Lin Tuo, Qingzhu Gao, Guiji Zhang, Yi Yang, Jie Xia, Li Liang, Jin Xiang, Xuanming Pan, Kai WangAbstract:Gluconeogenesis, generates glucose from small carbohydrate substrates, and drives the metabolic flux in parallel but opposite to glycolysis. The cytoplasmic isoform of phosphoenolpyruvate carboxykinase (PCK1 or PEPCK-C), a rate-limiting enzyme in gluconeogenesis, initiates the gluconeogenesis process and is reportedly dysregulated in multiple types of cancer. Gluconeogenesis mainly occurs in the liver during fasting, and previous studies have demonstrated that PCK1 acts as a tumor suppressor in hepatocellular carcinoma (HCC); however, the role of PCK1 in cancer progression remains incompletely understood. In the current study, we found that PCK1 expression was decreased in HCC as compared to adjacent normal liver tissues, and low PCK1 expression correlated with poor patient prognosis. Furthermore, overexpression of PCK1 suppressed reactive oxygen species (ROS) production and nuclear translocation of Nrf2 in hepatoma cells. In addition, thioredoxin reductase 1 (TXNRD1), an antioxidant enzyme regulated by the Nrf2/Keap1 pathway, was downregulated upon overexpression of PCK1 in HCC cell lines. Furthermore, we verified this axis using nude mouse xenograft model. Finally, we found that auranofin, a TXNRD1 inhibitor, enhanced the sensitivity of PCK1-knockout hepatoma cells to sorafenib-induced apoptosis. Taken together, our findings suggest that PCK1 deficiency promotes hepatoma cell proliferation via the induction of oxidative stress and the activation of transcription factor Nrf2, and that targeting the TXNRD1 antioxidant pathway sensitizes PCK1-knockout hepatoma cells to sorafenib treatment in vitro.
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Image_2_PCK1 Downregulation Promotes TXNRD1 Expression and Hepatoma Cell Growth via the Nrf2/Keap1 Pathway.JPEG
2018Co-Authors: Lin Tuo, Qingzhu Gao, Guiji Zhang, Yi Yang, Jie Xia, Li Liang, Jin Xiang, Xuanming Pan, Kai Wang, Ni TangAbstract:Gluconeogenesis, generates glucose from small carbohydrate substrates, and drives the metabolic flux in parallel but opposite to glycolysis. The cytoplasmic isoform of phosphoenolpyruvate carboxykinase (PCK1 or PEPCK-C), a rate-limiting enzyme in gluconeogenesis, initiates the gluconeogenesis process and is reportedly dysregulated in multiple types of cancer. Gluconeogenesis mainly occurs in the liver during fasting, and previous studies have demonstrated that PCK1 acts as a tumor suppressor in hepatocellular carcinoma (HCC); however, the role of PCK1 in cancer progression remains incompletely understood. In the current study, we found that PCK1 expression was decreased in HCC as compared to adjacent normal liver tissues, and low PCK1 expression correlated with poor patient prognosis. Furthermore, overexpression of PCK1 suppressed reactive oxygen species (ROS) production and nuclear translocation of Nrf2 in hepatoma cells. In addition, thioredoxin reductase 1 (TXNRD1), an antioxidant enzyme regulated by the Nrf2/Keap1 pathway, was downregulated upon overexpression of PCK1 in HCC cell lines. Furthermore, we verified this axis using nude mouse xenograft model. Finally, we found that auranofin, a TXNRD1 inhibitor, enhanced the sensitivity of PCK1-knockout hepatoma cells to sorafenib-induced apoptosis. Taken together, our findings suggest that PCK1 deficiency promotes hepatoma cell proliferation via the induction of oxidative stress and the activation of transcription factor Nrf2, and that targeting the TXNRD1 antioxidant pathway sensitizes PCK1-knockout hepatoma cells to sorafenib treatment in vitro.
