Glutaminolysis: A Hallmark of Cancer Metabolism

Yang, Lifeng; Venneti, Sriram; Nagrath, Deepak

doi:10.1146/annurev-bioeng-071516-044546

Cited by 552 publications

(453 citation statements)

References 168 publications

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“…Cancer cells use glutamine as a source of carbon for further anabolic pathways (oxidation) and glutamine is hereto transported into the cells by the alanine-serine-cysteine-transporter-2. As a nitrogen donor for the synthesis of DNA and RNA building blocks, glutamine is converted into glutamate [37, 38]. However, glutamine can also be exported out of the cell by antiporters in exchange for other non-essential amino acids through the L-type amino-acid transporter [39].…”

Section: Discussionmentioning

confidence: 99%

The plasma glutamate concentration as a complementary tool to differentiate benign PET-positive lung lesions from lung cancer

et al. 2018

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BackgroundPulmonary imaging often identifies suspicious abnormalities resulting in supplementary diagnostic procedures. This study aims to investigate whether the metabolic fingerprint of plasma allows to discriminate between patients with lung inflammation and patients with lung cancer.MethodsMetabolic profiles of plasma from 347 controls, 269 cancer patients and 108 patients with inflammation were obtained by 1H-NMR spectroscopy. Models to discriminate between groups were trained by PLS-LDA. A test set was used for independent validation. A ROC curve was built to evaluate the diagnostic performance of potential biomarkers.ResultsSensitivity, specificity, PPV and NPV of PET-CT to diagnose cancer are 96, 23, 76 and 71%. Metabolic profiles differentiate between cancer and inflammation with a sensitivity of 89%, a specificity of 87% and a MCE of 12%. Removal of the glutamate metabolite results in an increase of MCE (38%) and a decrease of both sensitivity and specificity (62%), demonstrating the importance of glutamate for discrimination. At the cut-off point 0.31 on the ROC curve, the relative glutamate concentration discriminates between cancer and inflammation with a sensitivity of 85%, a specificity of 81%, and an AUC of 0.88. PPV and NPV are 92 and 69%. In PET-positive patients with a relative glutamate level ≤ 0.31 the sensitivity to diagnose cancer reaches 100% with a PPV of 94%. In PET-negative patients, a relative glutamate level > 0.31 increases the specificity of PET from 23% to 58% and results in a high NPV of 100%. In case of discrepancy between SUVmax and the glutamate concentration, lung cancer is missed in 19% of the cases.ConclusionThis study indicates that the 1H-NMR-derived relative plasma concentration of glutamate allows discrimination between lung cancer and lung inflammation. A glutamate level ≤ 0.31 in PET-positive patients corresponds to the diagnosis of lung cancer with a higher specificity and PPV than PET-CT. Glutamate levels > 0.31 in patients with PET negative lung lesions is likely to correspond with inflammation. Caution is needed for patients with conflicting SUVmax values and glutamate concentrations. Confirmation is needed in a prospective study with external validation and by another analytical technique such as HPLC-MS.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4755-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

The plasma glutamate concentration as a complementary tool to differentiate benign PET-positive lung lesions from lung cancer

et al. 2018

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“…Glutamine, the most abundant amino acid in the blood, is metabolized through glutaminolysis in a two-step process to form α-KG, which is critical for producing oxaloacetate and citrate in the TCA cycle [85]. The enzyme glutaminase, which hydrolyzes glutamine to glutamate and whose activity correlates with tumor growth, is regulated by the oncogene c-Myc .…”

Section: Glutaminolysis C-myc and Rag-mtorc1 Signalingmentioning

confidence: 99%

A review of the basics of mitochondrial bioenergetics, metabolism, and related signaling pathways in cancer cells: Therapeutic targeting of tumor mitochondria with lipophilic cationic compounds

et al. 2018

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The present review is a sequel to the previous review on cancer metabolism published in this journal. This review focuses on the selective antiproliferative and cytotoxic effects of mitochondria-targeted therapeutics (MTTs) in cancer cells. Emerging research reveals a key role of mitochondrial respiration on tumor proliferation. Previously, a mitochondria-targeted nitroxide was shown to selectively inhibit colon cancer cell proliferation at submicromolar levels. This review is centered on the therapeutic use of MTTs and their bioenergetic profiling in cancer cells. Triphenylphosphonium cation conjugated to a parent molecule (e.g., vitamin-E or chromanol, ubiquinone, and metformin) via a linker alkyl chain is considered an MTT. MTTs selectively and potently inhibit proliferation of cancer cells and, in some cases, induce cytotoxicity. MTTs inhibit mitochondrial complex I activity and induce mitochondrial stress in cancer cells through generation of reactive oxygen species. MTTs in combination with glycolytic inhibitors synergistically inhibit tumor cell proliferation. This review discusses how signaling molecules traditionally linked to tumor cell proliferation affect tumor metabolism and bioenergetics (glycolysis, TCA cycle, and glutaminolysis).

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“…Glutamine, on the other hand, is an important source of nitrogen for the production of amino acids and NADPH. It also plays role in glutaminolysis, as a hallmark of cancer metabolism, and "glutamine addiction" [28][29][30] . Glutamine can also provide required nucleotides for DNA synthesis, is connected to the mTOR pathway and has roles in cell cycle control and nutrition status [30][31][32] .…”

Section: Resultsmentioning

confidence: 99%

How Human Lung Adenocarcinoma Cells React Towards Long-term Metabolic Stress; A Follow Up

Nakhjavani¹,

Shirazi²

2017

IJPER

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Introduction: A key challenge in fighting against cancer is cancer recurrence and resistance. Apart from the advances in the field of cancer treatment, the outcome is not still as high as expected. This may be partly due to the poor understanding about the true biology of a tumour. Tumour is a complex tissue and cells in its central parts bear nutrition deficiency and poor angiogenesis. Objective: The main aim of this study was to investigate the effect of long-term serum starvation on an in vitro model of human lung adenocarcinoma, A549 cell line. Methods: The cells bore serum starvation for 6 days and at 24-hour intervals, their proliferation, size, mitochondrial function and protein content was studied. Also, at 24-hour intervals and following at least 1 day of starvation, the cells were released in a 10% serum supplemented media and their reactions were studied as above. Results: The results demonstrated that despite the harsh conditions around the starved cells, they still proliferate and show increased mitochondrial function and protein content. Upon re-exposure to favourable conditions, this increase is more obvious. These observations were not recorded in control cells. Conclusion: It was concluded that following a long-term metabolic stress, these cells do not die, but become stronger and that can be a plausible explanation behind the difficulty in treatment of recurrent cancers.

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Glutaminolysis: A Hallmark of Cancer Metabolism

Cited by 552 publications

References 168 publications

The plasma glutamate concentration as a complementary tool to differentiate benign PET-positive lung lesions from lung cancer

The plasma glutamate concentration as a complementary tool to differentiate benign PET-positive lung lesions from lung cancer

A review of the basics of mitochondrial bioenergetics, metabolism, and related signaling pathways in cancer cells: Therapeutic targeting of tumor mitochondria with lipophilic cationic compounds

How Human Lung Adenocarcinoma Cells React Towards Long-term Metabolic Stress; A Follow Up

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