The glucose-responsive transcription factor ChREBP contributes to glucose-dependent anabolic synthesis and cell proliferation

Tong, Xuemei; Zhao, Fangping; Mancuso, Anthony A.; Gruber, Joshua J.; Thompson, Craig B.

doi:10.1073/pnas.0911316106

Cited by 136 publications

(140 citation statements)

References 31 publications

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“…The first possibility seems unlikely because Khk mRNA levels were lower in the ChREBP −/− model (37) . In support of the second possibility, gene microarrays in cells with ChREBP knockdown identified dihydrofolate reductase which is involved in purine biosynthesis in the down-regulated genes (70) , and genes involved in purine metabolism were also identified as ChREBP targets by chromatin immunoprecipitationsequencing (44) . A role for ChREBP in ATP homeostasis is also indicated by raised plasma uric acid levels in rats with partial ChREBP knock-down on a high-fructose diet (71) .…”

Section: Effects Of Fructose On Hepatic Phosphate Ester Inorganic Phmentioning

confidence: 95%

Dietary carbohydrate and control of hepatic gene expression: mechanistic links from ATP and phosphate ester homeostasis to the carbohydrate-response element-binding protein

Agius

2015

Proc. Nutr. Soc.

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Type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) are associated with elevated hepatic glucose production and fatty acid synthesis (de novolipogenesis (DNL)). High carbohydrate diets also increase hepatic glucose production and lipogenesis. The carbohydrate-response element-binding protein (ChREBP, encoded byMLXIPL) is a transcription factor with a major role in the hepatic response to excess dietary carbohydrate. Because its target genes include pyruvate kinase (PKLR) and enzymes of lipogenesis, it is regarded as a key regulator for conversion of dietary carbohydrate to lipid for energy storage. An alternative hypothesis for ChREBP function is to maintain hepatic ATP homeostasis by restraining the elevation of phosphate ester intermediates in response to elevated glucose. This is supported by the following evidence: (i) A key stimulus for ChREBP activation and induction of its target genes is elevation of phosphate esters; (ii) target genes of ChREBP include key negative regulators of the hexose phosphate ester pool (GCKR,G6PC,SLC37A4) and triose phosphate pool (PKLR); (iii) ChREBP knock-down models have elevated hepatic hexose phosphates and triose phosphates and compromised ATP phosphorylation potential; (iv) gene defects inG6PCandSLC37A4and common variants ofMLXIPL,GCKRandPKLRin man are associated with elevated hepatic uric acid production (a marker of ATP depletion) or raised plasma uric acid levels. It is proposed that compromised hepatic phosphate homeostasis is a contributing factor to the elevated hepatic glucose production and lipogenesis that associate with type 2 diabetes, NAFLD and excess carbohydrate in the diet.

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Section: Effects Of Fructose On Hepatic Phosphate Ester Inorganic Phmentioning

confidence: 95%

Dietary carbohydrate and control of hepatic gene expression: mechanistic links from ATP and phosphate ester homeostasis to the carbohydrate-response element-binding protein

Agius

2015

Proc. Nutr. Soc.

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“…To sustain their high proliferative rate, cancer cells adapt their metabolism towards the aerobic glycolysis (Tong et al 2009). Thyroid cancer cells also show a high rate of glycolysis (Andrade et al 2012).…”

Section: Discussionmentioning

confidence: 99%

PTEN regulates plasma membrane expression of glucose transporter 1 and glucose uptake in thyroid cancer cells

Morani

Phadngam

Follo

et al. 2014

Journal of Molecular Endocrinology

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Glucose represents an important source of energy for the cells. Proliferating cancer cells consume elevated quantity of glucose, which is converted into lactate regardless of the presence of oxygen. This phenomenon, known as the Warburg effect, has been proven to be useful for imaging metabolically active tumours in cancer patients by 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET). Glucose is internalised in the cells by glucose transporters (GLUTs) belonging to the GLUT family. GLUT1 (SLC2A1) is the most prevalent isoform in more aggressive and less differentiated thyroid cancer histotypes. In a previous work, we found that loss of expression of PTEN was associated with increased expression of GLUT1 on the plasma membrane (PM) and probability of detecting thyroid incidentalomas by FDG-PET. Herein, we investigated the molecular pathways that govern the expression of GLUT1 on the PM and the glucose uptake in WRO (expressing WT PTEN) and FTC133 (PTEN null) follicular thyroid cancer cells cultured under glucose-depleted conditions. The membrane expression of GLUT1 was enhanced in glucose-deprived cells. Through genetic manipulations of PTEN expression, we could demonstrate that the lack of this oncosuppressor has a dominant effect on the membrane expression of GLUT1 and glucose uptake. We conclude that loss of function of PTEN increases the probability of cancer detection by FDG-PET or other glucose-based imaging diagnosis.

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“…In the presence of glucose, ChREBP activates genes with carbohydrate-responsive elements and promotes glycolysis. Downregulation of ChREBP switches cell metabolism from aerobic glycolysis to respiration and inhibits proliferation of tumor cells (Tong et al, 2009).…”

Section: Sensing Glucose Deprivationmentioning

confidence: 99%

Sugar-free approaches to cancer cell killing

et al. 2010

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Tumors show an increased rate of glucose uptake and utilization. For this reason, glucose analogs are used to visualize tumors by the positron emission tomography technique, and inhibitors of glycolytic metabolism are being tested in clinical trials. Upregulation of glycolysis confers several advantages to tumor cells: it promotes tumor growth and has also been shown to interfere with cell death at multiple levels. Enforcement of glycolysis inhibits apoptosis induced by cytokine deprivation. Conversely, antiglycolytic agents enhance cell death induced by radio-and chemotherapy. Synergistic effects are likely due to regulation of the apoptotic machinery, as glucose regulates activation and levels of proapoptotic BH3-only proteins such as Bim, Bad, Puma and Noxa, as well as the antiapoptotic Bcl-2 family of proteins. Moreover, inhibition of glucose metabolism sensitizes cells to death ligands. Glucose deprivation and antiglycolytic drugs induce tumor cell death, which can proceed through necrosis or through mitochondrial or caspase-8-mediated apoptosis. We will discuss how oncogenic pathways involved in metabolic stress signaling, such as p53, AMPK (adenosine monophosphate-activated protein kinase) and Akt/mTOR (mammalian target of rapamycin), influence sensitivity to inhibition of glucose metabolism. Finally, we will analyze the rationale for the use of antiglycolytic inhibitors in the clinic, either as single agents or as a part of combination therapies.

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The glucose-responsive transcription factor ChREBP contributes to glucose-dependent anabolic synthesis and cell proliferation

Cited by 136 publications

References 31 publications

Dietary carbohydrate and control of hepatic gene expression: mechanistic links from ATP and phosphate ester homeostasis to the carbohydrate-response element-binding protein

Dietary carbohydrate and control of hepatic gene expression: mechanistic links from ATP and phosphate ester homeostasis to the carbohydrate-response element-binding protein

PTEN regulates plasma membrane expression of glucose transporter 1 and glucose uptake in thyroid cancer cells

Sugar-free approaches to cancer cell killing

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