Glutamine Metabolism in Cancer: Understanding the Heterogeneity

Cluntun, Ahmad A.; Lukey, Michael J.; Cerione, Richard A.; Locasale, Jason W.

doi:10.1016/j.trecan.2017.01.005

Cited by 562 publications

(422 citation statements)

References 103 publications

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“…41,42 Studies have shown glutamine metabolism reprogramming in a tissue-dependent and tumor-heterogeneous manner. 43 Its role in disparities remains to be investigated. Lysine catabolism is important in the early stages of liver metastasis in colorectal cancer, but it is not essential for growth in liver metastases.…”

Section: Discussionmentioning

confidence: 99%

Large‐scale profiling of serum metabolites in African American and European American patients with bladder cancer reveals metabolic pathways associated with patient survival

Vantaku

Donepudi

Piyarathna

et al. 2019

Cancer

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BACKGROUND: African Americans (AAs) experience a disproportionally high rate of bladder cancer (BLCA) deaths even though their incidence rates are lower than those of other patient groups. Using a metabolomics approach, this study investigated how AA BLCA may differ molecularly from European Americans (EAs) BLCA, and it examined serum samples from patients with BLCA with the aim of identifying druggable metabolic pathways in AA patients. METHODS: Targeted metabolomics was applied to measure more than 300 metabolites in serum samples from 2 independent cohorts of EA and AA patients with BLCA and healthy EA and AA controls via liquid chromatography-mass spectrometry, and this was followed by the identification of altered metabolic pathways with a focus on AA BLCA. A subset of the differential metabolites was validated via absolute quantification with the Biocrates AbsoluteIDQ p180 kit. The clinical significance of the findings was further examined in The Cancer Genomic Atlas BLCA data set. RESULTS: Fifty-three metabolites, mainly related to amino acid, lipid, and nucleotide metabolism, were identified that showed significant differences in abundance between AA and EA BLCA. For example, the levels of taurine, glutamine, glutamate, aspartate, and serine were elevated in serum samples from AA patients versus EA patients. By mapping these metabolites to genes, this study identified significant relations with regulators of metabolism such as malic enzyme 3, prolyl 3-hydroxylase 2, and lysine demethylase 2A that predicted patient survival exclusively in AA patients with BLCA. CONCLUSIONS: This metabolic profile of serum samples might be used to assess risk progression in AA BLCA. These first-in-field findings describe metabolic alterations in AA BLCA and emphasize a potential biological basis for BLCA health disparities. Cancer 2019;125:921-932.

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Section: Discussionmentioning

confidence: 99%

Large‐scale profiling of serum metabolites in African American and European American patients with bladder cancer reveals metabolic pathways associated with patient survival

Vantaku

Donepudi

Piyarathna

et al. 2019

Cancer

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“…The amide nitrogen of glutamine is most often used to synthesize asparagine and nucleotide, concomitantly with production of glutamate (27). Glutamate can be used for multiple purposes, but it can be readily synthesized through the transamination between α-ketoglutarate and other amino acids, thus it is dispensable to cancer cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

Coordinative Metabolism of Glutamine Carbon and Nitrogen in proliferating Cancer Cells Under Hypoxia

Wang

Bai

Ruan

et al. 2018

Preprint

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Under hypoxia, most of glucose is converted to secretory lactate, which leads to the lack of carbon source from glucose and thus the overuse of glutamine-carbon. However, under such a condition how glutamine nitrogen is disposed to avoid releasing potentially toxic ammonia remains to be determined. Here we identify a metabolic flux of glutamine to secretory dihydroorotate under hypoxia. We found that glutamine nitrogen is indispensable to nucleotide biosynthesis, but enriched in dihyroorotate and orotate rather than processing to its downstream uridine monophosphate under hypoxia. Dihyroorotate, not orotate, is then secreted out of cells. The specific metabolic pathway occurs in vivo and is required for tumor growth. Such a metabolic pathway renders glutamine mainly to acetyl coenzyme A for lipogenesis, with the rest carbon and nitrogen being safely removed. Our results reveal how glutamine carbon and nitrogen are coordinatively metabolized under hypoxia, and provide a comprehensive understanding on glutamine metabolism.Significance: Tumor cells often addict to glutamine, and particularly utilize its carbon for lipogenesis under hypoxia. We reveal that tumor cells package the excessive glutamine-nitrogen into secretory dihydroorotate, instead of toxic ammonia. This specifically reprogrammed pathway supports in vivo tumor growth, and could offer diagnostic markers and therapeutic targets for cancers.

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“…Most studies reported that lower levels of amino acids may be related to a higher protein demand in cancer cells to support their rapid growth and proliferation . During glutaminolysis, a central distinctive feature of cancer metabolism, glutamate converts glutamine to α‐ketoglutarate, which is introduced into the tricarboxylic cycle to produce energy and anabolic carbons for the synthesis of amino acids, nucleotides, and lipids . Although no significant alterations in glutamine concentrations in primary breast cancer patient plasma were observed, its interchangeable substrate, glutamate, was found at significantly lower concentrations in primary breast cancer patients compared to those in healthy controls.…”

Section: Discussionmentioning

confidence: 98%

A plasma metabolite panel as biomarkers for early primary breast cancer detection

Yuan

Schafferer

Tang

et al. 2019

Intl Journal of Cancer

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In recent years, metabolites have attracted substantial attention as promising novel biomarkers of various diseases. However, breast cancer plasma metabolite studies are still in their infancy. Here, we investigated the potential of metabolites to serve as minimally invasive, early detection markers of primary breast cancer. We profiled metabolites extracted from the plasma of primary breast cancer patients and healthy controls using tandem mass spectrometry (UHPLC‐MS/MS and FIA‐MS/MS). Two metabolites were found to be upregulated, while 16 metabolites were downregulated in primary breast cancer patients compared to healthy controls in both the training and validation cohorts. A panel of seven metabolites was selected by LASSO regression analysis. This panel could differentiate primary breast cancer patients from healthy controls, with an AUC of 0.87 (95% CI: 0.81 ~ 0.92) in the training cohort and an AUC of 0.80 (95% CI: 0.71 ~ 0.87) in the validation cohort. These significantly differentiated metabolites are mainly involved in the amino acid metabolism and breast cancer cell growth pathways. In conclusion, using a metabolomics approach, we identified metabolites that have potential value for development of a multimarker blood‐based test to complement and improve early breast cancer detection. The panel identified herein might be part of a prescreening tool, especially for younger women or for closely observing women with certain risks, to facilitate decision making regarding which individuals should undergo further diagnostic tests. In the future, the combination of metabolites and other blood‐based molecular marker sets, such as DNA methylation, microRNA, and cell‐free DNA mutation markers, will be an attractive option.

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Glutamine Metabolism in Cancer: Understanding the Heterogeneity

Cited by 562 publications

References 103 publications

Large‐scale profiling of serum metabolites in African American and European American patients with bladder cancer reveals metabolic pathways associated with patient survival

Large‐scale profiling of serum metabolites in African American and European American patients with bladder cancer reveals metabolic pathways associated with patient survival

Coordinative Metabolism of Glutamine Carbon and Nitrogen in proliferating Cancer Cells Under Hypoxia

A plasma metabolite panel as biomarkers for early primary breast cancer detection

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