Glutamine at focus: versatile roles in cancer

Vitto, Humberto De; Pérez-Valencia, Juan Alberto; Radosevich, James A.

doi:10.1007/s13277-015-4671-9

Cited by 39 publications

(35 citation statements)

References 167 publications

(230 reference statements)

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“…Glutamate can in turn be converted by glutamate dehydrogenase (GLUD) or transamination into α-ketoglutarate to enter the TCA cycle (De Vitto et al, 2015). Oxidative metabolism of α-ketoglutarate in the TCA cycle generates ATP and 4C units (e.g., oxaloacetate).…”

Section: Mitochondria Integrate Catabolism Anabolism and Signalingmentioning

confidence: 99%

Mitochondria and Cancer

2016

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Decades ago Otto Warburg observed that cancers ferment glucose in the presence of oxygen, suggesting that defects in mitochondrial respiration may be the underlying cause of cancer. We now know that the genetic events, which drive aberrant cancer cell proliferation, also alter biochemical metabolism including promoting aerobic glycolysis, but do not typically impair mitochondrial function. Mitochondria supply energy, provide building blocks for new cells, and control redox homeostasis, oncogenic signaling, innate immunity and apoptosis. Indeed, mitochondrial biogenesis and quality control are often upregulated in cancers. While some cancers have mutations in nuclear-encoded mitochondrial tricarboxylic acid (TCA) cycle enzymes that produce oncogenic metabolites, there is negative selection for pathogenic mitochondrial genome mutations. Eliminating mitochondrial DNA limits tumorigenesis and rare human tumors with mutant mitochondrial genomes are relatively benign. Thus, mitochondria play a central and multi-functional role in malignant tumor progression, and targeting mitochondria provides therapeutic opportunities.

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Section: Mitochondria Integrate Catabolism Anabolism and Signalingmentioning

confidence: 99%

Mitochondria and Cancer

2016

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“…For more information about glutamine metabolism in cancer, the reader is referred to the following reviews [109,112]. …”

Section: Secondary Glutamine Synthetase Deficiencymentioning

confidence: 99%

Minireview on Glutamine Synthetase Deficiency, an Ultra-Rare Inborn Error of Amino Acid Biosynthesis

Spodenkiewicz

Dı́ez-Fernández

Rüfenacht

et al. 2016

Biology

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Glutamine synthetase (GS) is a cytosolic enzyme that produces glutamine, the most abundant free amino acid in the human body. Glutamine is a major substrate for various metabolic pathways, and is thus an important factor for the functioning of many organs; therefore, deficiency of glutamine due to a defect in GS is incompatible with normal life. Mutations in the human GLUL gene (encoding for GS) can cause an ultra-rare recessive inborn error of metabolism—congenital glutamine synthetase deficiency. This disease was reported until now in only three unrelated patients, all of whom suffered from neonatal onset severe epileptic encephalopathy. The hallmark of GS deficiency in these patients was decreased levels of glutamine in body fluids, associated with chronic hyperammonemia. This review aims at recapitulating the clinical history of the three known patients with congenital GS deficiency and summarizes the findings from studies done along with the work-up of these patients. It is the aim of this paper to convince the reader that (i) this disorder is possibly underdiagnosed, since decreased concentrations of metabolites do not receive the attention they deserve; and (ii) early detection of GS deficiency may help to improve the outcome of patients who could be treated early with metabolites that are lacking in this condition.

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“…The genetic reprogramming of some cancer types to make use of glutamine as an alternative nutrient source includes increased expression of proteins that act as transporters of amino acids, such as SLC1A5 (ASTC2), or the upregulation of enzymes that catalyze the metabolism of glutamine, for example, glutaminase . Proliferating cancer cells use glutamine as a nitrogen donor for the synthesis of nucleotide precursors, and following the conversion to glutamate, the generation of the amino acids alanine and aspartate . The conversion to glutamate also enables cells to use glutamine as a carbon source for the production of α‐ketoglutarate through the activity of glutamine dehydrogenase or an aminotransferase, including PSAT1 .…”

Section: Introductionmentioning

confidence: 99%

“…15 Proliferating cancer cells use glutamine as a nitrogen donor for the synthesis of nucleotide precursors, and following the conversion to glutamate, the generation of the amino acids alanine and aspartate. 4,16,17 The conversion to glutamate also enables cells to use glutamine as a carbon source for the production of α-ketoglutarate through the activity of glutamine dehydrogenase or an aminotransferase, including PSAT1. 4,16,17 Strategies to exploit the dependence of some tumor types on glutamine that are under development include the use of glutamine transport or enzyme inhibitors.…”

Section: Introductionmentioning

confidence: 99%

“…4,16,17 The conversion to glutamate also enables cells to use glutamine as a carbon source for the production of α-ketoglutarate through the activity of glutamine dehydrogenase or an aminotransferase, including PSAT1. 4,16,17 Strategies to exploit the dependence of some tumor types on glutamine that are under development include the use of glutamine transport or enzyme inhibitors. [18][19][20] Ewing sarcoma (EWS), a soft tissue and bone tumor, primarily occurs in adolescents and young adults.…”

Section: Introductionmentioning

confidence: 99%

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EWS‐FLI1 reprograms the metabolism of Ewing sarcoma cells via positive regulation of glutamine import and serine‐glycine biosynthesis

Sen

Cross

Lorenzi

et al. 2018

Molecular Carcinogenesis

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Ewing sarcoma (EWS) is a soft tissue and bone tumor that occurs primarily in adolescents and young adults. In most cases of EWS, the chimeric transcription factor, EWS‐FLI1 is the primary oncogenic driver. The epigenome of EWS cells reflects EWS‐FLI1 binding and activation or repression of transcription. Here, we demonstrate that EWS‐FLI1 positively regulates the expression of proteins required for serine‐glycine biosynthesis and uptake of the alternative nutrient source glutamine. Specifically, we show that EWS‐FLI1 activates expression of PHGDH, PSAT1, PSPH, and SHMT2. Using cell‐based studies, we also establish that EWS cells are dependent on glutamine for cell survival and that EWS‐FLI1 positively regulates expression of the glutamine transporter, SLC1A5 and two enzymes involved in the one‐carbon cycle, MTHFD2 and MTHFD1L. Inhibition of serine‐glycine biosynthesis in EWS cells impacts their redox state leading to an accumulation of reactive oxygen species, DNA damage, and apoptosis. Importantly, analysis of EWS primary tumor transcriptome data confirmed that the aforementioned genes we identified as regulated by EWS‐FLI1 exhibit increased expression compared with normal tissues. Furthermore, retrospective analysis of an independent data set generated a significant stratification of the overall survival of EWS patients into low‐ and high‐risk groups based on the expression of PHGDH, PSAT1, PSPH, SHMT2, SLC1A5, MTHFD2, and MTHFD1L. In summary, our study demonstrates that EWS‐FLI1 reprograms the metabolism of EWS cells and that serine‐glycine metabolism or glutamine uptake are potential targetable vulnerabilities in this tumor type.

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Glutamine at focus: versatile roles in cancer

Cited by 39 publications

References 167 publications

Mitochondria and Cancer

Mitochondria and Cancer

Minireview on Glutamine Synthetase Deficiency, an Ultra-Rare Inborn Error of Amino Acid Biosynthesis

EWS‐FLI1 reprograms the metabolism of Ewing sarcoma cells via positive regulation of glutamine import and serine‐glycine biosynthesis

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