Gluconeogenesis in cancer: Door wide open

Leithner, Katharina; Hrzenjak, Andelko; Olschewski, Horst

doi:10.1073/pnas.1415680111

Cited by 11 publications

(10 citation statements)

References 5 publications

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“…2a ), Nur77 might regulate glucose metabolism to inhibit HCC cell proliferation. Again, inhibition of gluconeogenesis by p53 may lead to tumour suppression 30 31 ; however, Nur77 still regulated glucose metabolism in p53-null Hep3B cells ( Supplementary Fig. 2b ).…”

Section: Resultsmentioning

confidence: 99%

Nur77 suppresses hepatocellular carcinoma via switching glucose metabolism toward gluconeogenesis through attenuating phosphoenolpyruvate carboxykinase sumoylation

et al. 2017

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Gluconeogenesis, an essential metabolic process for hepatocytes, is downregulated in hepatocellular carcinoma (HCC). Here we show that the nuclear receptor Nur77 is a tumour suppressor for HCC that regulates gluconeogenesis. Low Nur77 expression in clinical HCC samples correlates with poor prognosis, and a Nur77 deficiency in mice promotes HCC development. Nur77 interacts with phosphoenolpyruvate carboxykinase (PEPCK1), the rate-limiting enzyme in gluconeogenesis, to increase gluconeogenesis and suppress glycolysis, resulting in ATP depletion and cell growth arrest. However, PEPCK1 becomes labile after sumoylation and is degraded via ubiquitination, which is augmented by the p300 acetylation of ubiquitin-conjugating enzyme 9 (Ubc9). Although Nur77 attenuates sumoylation and stabilizes PEPCK1 via impairing p300 activity and preventing the Ubc9-PEPCK1 interaction, Nur77 is silenced in HCC samples due to Snail-mediated DNA methylation of the Nur77 promoter. Our study reveals a unique mechanism to suppress HCC by switching from glycolysis to gluconeogenesis through Nur77 antagonism of PEPCK1 degradation.

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Section: Resultsmentioning

confidence: 99%

Nur77 suppresses hepatocellular carcinoma via switching glucose metabolism toward gluconeogenesis through attenuating phosphoenolpyruvate carboxykinase sumoylation

et al. 2017

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“…Therefore, the slightly increased viability by addition of galactose indicated that the pentose phosphate pathway partially contributed to cell viability, but was not the key pathway for GOT1-null cells to survive glucose deprivation. Metformin is a well-known gluconeogenesis inhibitor that has been shown to cause accumulation of NADH in cells [ 31 ]. A similar pattern of NADH accumulation was found in GOT1-null 143B cells grown in nutrient-depleted conditions.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of glutamate oxaloacetate transaminase 1 in cancer cell lines results in altered metabolism with increased dependency of glucose

Zhou

Curbo

Li³

et al. 2018

BMC Cancer

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BackgroundGlutamate oxaloacetate transaminase 1 (GOT1) regulates cellular metabolism through coordinating the utilization of carbohydrates and amino acids to meet nutrient requirements. KRAS mutated cancer cells were recently shown to rely on GOT1 to support long-term cell proliferation. The aim of the present study was to address the role of GOT1 in the metabolic adaption of cancer cells.MethodsGOT1-null and knockdown cell lines were established through CRISPR/Cas9 and shRNA techniques. The growth properties, colony formation ability, autophagy and selected gene expression profiles were analysed. Glucose deprivation decreased the viability of the GOT1-null cells and rescue experiments were conducted with selected intermediates. The redox NADH/NAD+ homeostasis as well as lactate secretion were determined. GOT1 expression levels and correlation with survival rates were analysed in selected tumor databases.ResultsInhibition of GOT1 sensitized the cancer cells to glucose deprivation, which was partially counteracted by oxaloacetate and phosphoenol pyruvate, metabolic intermediates downstream of GOT1. Moreover, GOT1-null cells accumulated NADH and displayed a decreased ratio of NADH/NAD+ with nutrient depletion. The relevance of GOT1 as a potential target in cancer therapy was supported by a lung adenocarcinoma RNA-seq data set as well as the GEO:GSE database of metastatic melanoma where GOT1 expression was increased. High levels of GOT1 were further linked to poor survival as analysed by the GEPIA web tool, in thyroid and breast carcinoma and in lung adenocarcinoma.ConclusionsOur study suggests an important role of GOT1 to coordinate the glycolytic and the oxidative phosphorylation pathways in KRAS mutated cancer cells. GOT1 is crucial to provide oxaloacetate at low glucose levels, likely to maintain the redox homeostasis. Our data suggest GOT1 as a possible target in cancer therapy.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4443-1) contains supplementary material, which is available to authorized users.

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“…This was associated with decreased expression of gluconeogenic genes and autophagy in tumors, but no major changes in other metabolic pathways were observed. Whilst activation of Insulin/IGF-1 in tumors may be detrimental (5), recent evidence indicate that inhibition of gluconeogenesis may lead to prevention of tumor growth (58). Further studies are necessary to explore the role of VEGFR-1 in local tumor metabolism.…”

Section: Discussionmentioning

confidence: 99%

PlGF/VEGFR-1 Signaling Promotes Macrophage Polarization and Accelerated Tumor Progression in Obesity

Incio

Tam

Rahbari

et al. 2016

Clinical Cancer Research

115

118

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PURPOSE Obesity promotes pancreatic and breast cancer progression via mechanisms that are poorly understood. Although obesity is associated with increased systemic levels of placental growth factor (PlGF), the role of PlGF in obesity-induced tumor progression is not known. PlGF and its receptor vascular endothelial growth factor receptor-1 (VEGFR-1) have been shown to modulate tumor angiogenesis and promote tumor-associated macrophage (TAM) recruitment and activity. Here, we hypothesized that increased activity of PlGF/VEGFR-1 signaling mediates obesity-induced tumor progression by augmenting tumor angiogenesis and TAM recruitment/activity. EXPERIMENTAL DESIGN We established diet-induced obese mouse models of wild type C57BL/6, VEGFR-1 tyrosine kinase (TK)-null or PlGF null mice, and evaluated the role of PlGF/VEGFR-1 signaling in pancreatic and breast cancer mouse models and in human samples. RESULTS We found that obesity increased TAM infiltration, tumor growth and metastasis in pancreatic cancers, without affecting vessel density. Ablation of VEGFR-1 signaling prevented obesity-induced tumor progression and shifted the tumor immune environment towards an anti-tumor phenotype. Similar findings were observed in a breast cancer model. Obesity was associated with increased systemic PlGF, but not VEGF-A or VEGF-B, in pancreatic and breast cancer patients and in various mouse models of these cancers. Ablation of PlGF phenocopied the effects of VEGFR-1-TK deletion on tumors in obese mice. PlGF/VEGFR-1-TK deletion prevented weight gain in mice fed a high-fat diet, but exacerbated hyperinsulinemia. Addition of metformin not only normalized insulin levels but also enhanced anti-tumor immunity. CONCLUSIONS Targeting PlGF/VEGFR-1 signaling reprograms the tumor immune microenvironment and inhibits obesity-induced acceleration of tumor progression.

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Gluconeogenesis in cancer: Door wide open

Cited by 11 publications

References 5 publications

Nur77 suppresses hepatocellular carcinoma via switching glucose metabolism toward gluconeogenesis through attenuating phosphoenolpyruvate carboxykinase sumoylation

Nur77 suppresses hepatocellular carcinoma via switching glucose metabolism toward gluconeogenesis through attenuating phosphoenolpyruvate carboxykinase sumoylation

Inhibition of glutamate oxaloacetate transaminase 1 in cancer cell lines results in altered metabolism with increased dependency of glucose

PlGF/VEGFR-1 Signaling Promotes Macrophage Polarization and Accelerated Tumor Progression in Obesity

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