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Cited by 1,021Cancer, Hypoxia, and MetabolismAmino Acid Enzymes and MetabolismCancer, Lipids, and Metabolism

Glutamine reliance in cell metabolism

Open access
Yoo, Hee Chan, Yu, Ya Chun, Sung, Yulseung, Han, Jung Min·2020·Experimental & Molecular Medicine
DOI 10.1038/s12276-020-00504-8PMC PMC8080614
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Abstract

As knowledge of cell metabolism has advanced, glutamine has been considered an important amino acid that supplies carbon and nitrogen to fuel biosynthesis. A recent study provided a new perspective on mitochondrial glutamine metabolism, offering mechanistic insights into metabolic adaptation during tumor hypoxia, the emergence of drug resistance, and glutaminolysis-induced metabolic reprogramming and presenting metabolic strategies to target glutamine metabolism in cancer cells. In this review, we introduce the various biosynthetic and bioenergetic roles of glutamine based on the compartmentalization of glutamine metabolism to explain why cells exhibit metabolic reliance on glutamine. Additionally, we examined whether glutamine derivatives contribute to epigenetic regulation associated with tumorigenesis. In addition, in discussing glutamine transporters, we propose a metabolic target for therapeutic intervention in cancer.

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Written from the paper’s full text.

TL;DR

This review synthesizes how glutamine's compartmentalized metabolism supplies carbon and nitrogen for biosynthesis, bioenergetics, redox control, and epigenetic regulation, explaining why many cancer cells become "glutamine addicted." It also surveys oncogenic drivers of glutamine dependence and the therapeutic strategies (transporters, GLS inhibitors, prodrugs) being pursued against it.

Key findings

  • Glutamine is conditionally essential in transformed cells because consumption exceeds endogenous synthesis; it feeds TCA anaplerosis, nucleotide/NEAA/glutathione synthesis, and NADPH production. In K-Ras/Akt-transformed cells, ~60% of total FADH2 and NADH2 was reported to derive from glutamine versus ~30% from glucose.
  • Nucleotide biosynthesis consumes glutamine-derived nitrogen at defined stoichiometries: two glutamines to generate IMP, one more for IMP→GMP, one for the CPS step of pyrimidine synthesis, and one more for UTP→CTP; in K-Ras/LKB1-mutant lung cancer, mitochondrial CPS1 is the major rate-limiting enzyme.
  • Glutamine-derived α-KG is a cofactor for 2-OGDDs (JmjC histone demethylases, TET DNA demethylases), linking glutaminolysis to epigenetic state; mutant IDH1/2 converts α-KG to R-2-HG, and succinate/fumarate accumulation similarly inhibits these enzymes, producing hypermethylation phenotypes.
  • Under hypoxia, HIF-2α (not HIF-1α) drives expression of the mitochondrial SLC1A5 variant and shifts glutamine toward reductive carboxylation to citrate for lipid synthesis; L-2-HG generated by LDHA/MDH under hypoxia or acidic pH further modulates methylation and stabilizes HIF-1α.

Methods

  • Narrative review; no primary experiments, datasets, or systematic search protocol are reported.
  • The authors organize the literature around glutamine metabolic pathways (transport, glutaminolysis, nucleotide/NEAA/glutathione synthesis), hypoxia adaptation, epigenetic control, oncometabolites (R-2-HG, succinate, fumarate), energy production, oncogenic signaling (MYC, K-Ras, PIK3CA, mTORC1), and therapeutic targeting.
  • Evidence cited is drawn from prior in vitro, in vivo, and clinical studies, including the authors' own prior work on the SLC1A5 mitochondrial variant (ref. 16).

Limitations

  • Stated by the paper: the mechanism by which asparagine supplementation rescues glutamine-deprived cells "is still unknown"; the extent to which glutamine supports tumor growth in vivo "remains elusive" given reports that K-Ras lung tumors and glioblastoma rely more on glucose/glutamate; no compound yet inhibits SLC1A5 with good sensitivity and specificity (GPNA also inhibits SLC38A1; V-9302 works even in SLC1A5 knockouts); and no glutaminolysis-targeting agent has yet been used clinically.
  • Evident from the text: as a review, it presents no new data and its claims rest on cited primary studies of varying models; several proposed links (e.g., SLC1A5-variant control of epigenetic regulation, glutamine–autophagy–metabolic remodeling connections) are explicitly flagged as requiring further investigation.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s12276-020-00504-8

Cites

212 of 212 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

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  • Premisecitation

    Glutamine supports mitochondrial oxidative metabolism when pyruvate derived from glucose is converted into lactate and secreted.

    “The major findings are that aerobic glycolysis is not a symptom of impaired mitochondrial function, and that glutamine supports mitochondrial oxidative metabolism when pyruvate derived from glucose is converted into lactate and secreted2–4.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [2] DeBerardinis, R. J. & Cheng, T. Q’s next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 29, 313–324 (2010). source

      Not checked in the free run.

    • cites [3] Hensley, C. T., Wasti, A. T. & DeBerardinis, R. J. Glutamine and cancer: cell biology, physiology, and clinical opportunities. J. Clin. Invest. 123, 3678–3684 (2013). source

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    • cites [4] Altman, B. J., Stine, Z. E. & Dang, C. V. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat. Rev. Cancer 16, 749 (2016). source

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  • Premisecitation

    Specific genetic interference with glutaminase (GLS) inhibits tumor cell growth.

    “specific genetic interference with glutaminase (GLS) inhibits tumor cell growth13.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Lobo, C. et al. Inhibition of glutaminase expression by antisense mRNA decreases growth and tumourigenicity of tumour cells. Biochem. J. 348, 257–261 (2000). source

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  • Premisecitation

    Glutamine is essential in cancer cells because transformed cells consume glutamine at a rate exceeding that of glutamine biosynthesis.

    “Glutamine, which is a nonessential amino acid (NEAA) due to the endogenous glutamine biosynthesis pathway, is currently considered essential in cancer cells because transformed cells consume glutamine at a rate exceeding that of glutamine biosynthesis5.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Zhang, J., Pavlova, N. N. & Thompson, C. B. Cancer cell metabolism: the essential role of the nonessential amino acid, glutamine. Embo J. 36, 1302–1315 (2017). source

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  • Premisecitation

    Aerobic glycolysis is not a symptom of impaired mitochondrial function.

    “The major findings are that aerobic glycolysis is not a symptom of impaired mitochondrial function, and that glutamine supports mitochondrial oxidative metabolism when pyruvate derived from glucose is converted into lactate and secreted2–4.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [2] DeBerardinis, R. J. & Cheng, T. Q’s next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 29, 313–324 (2010). source

      Not checked in the free run.

    • cites [3] Hensley, C. T., Wasti, A. T. & DeBerardinis, R. J. Glutamine and cancer: cell biology, physiology, and clinical opportunities. J. Clin. Invest. 123, 3678–3684 (2013). source

      Not checked in the free run.

    • cites [4] Altman, B. J., Stine, Z. E. & Dang, C. V. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat. Rev. Cancer 16, 749 (2016). source

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  • Premisecitation

    Glutamine is a major nutrient source for oxidative metabolism in some cancer cell lines.

    “glutamine has been confirmed to be a major nutrient source for oxidative metabolism in some cancer cell lines10–12”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [10] Eagle, H. Nutrition needs of mammalian cells in tissue culture. Science 122, 501–514 (1955). source

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    • cites [11] Kovacevic, Z. & Morris, H. P. The role of glutamine in the oxidative metabolism of malignant cells. Cancer Res. 32, 326–333 (1972).

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    • cites [12] Reitzer, L. J., Wice, B. M. & Kennell, D. Evidence that glutamine, not sugar, is the major energy source for cultured HeLa cells. J. Biol. Chem. 254, 2669–2676 (1979). source

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  • Classified as probably not a substantial claim. 4
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    Premisecitation

    CB-839, the first glutaminase inhibitor, has entered several clinical trials.

    “Moreover, CB-839, the first glutaminase inhibitor, has entered several clinical trials14,15.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] Gross, M. I. et al. Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol. Cancer Ther. 13, 890–901 (2014). source

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    • cites [15] Kizilbash, S. H. et al. The addition of CB-839 to temozolomide significantly reduces glioma aspartate and glutamate in an IDH mutated patient derived glioma xenograft model. Cancer Res. https://doi.org/10.1158/1538-7445.AM2019-3870 (2019). source

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    Premisecitation

    Glutamine deprivation suppresses cancer growth and induces cell death in several cancers.

    “Thus, glutamine deprivation suppresses cancer growth and even induces cell death in several cancers6,7.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [6] Qing, G. et al. ATF4 regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation. Cancer Cell 22, 631–644 (2012). source

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    • cites [7] Chen, L. & Cui, H. Targeting glutamine induces apoptosis: a cancer therapy approach. Int. J. Mol. Sci. 16, 22830–22855 (2015). source

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    Premisecitation

    α-KG-derived metabolites such as succinate and fumarate generated via glutaminolysis are considered oncometabolites contributing to tumorigenesis.

    “In addition to pyruvate-derived acetyl-CoA, α-KG-derived metabolites (e.g., succinate and fumarate) generated via glutaminolysis are considered oncometabolites contributing to tumorigenesis23.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Yang, L. F., Venneti, S. & Nagrath, D. Glutaminolysis: a hallmark of cancer metabolism. Annu. Rev. Biomed. Eng. 19, 163–194 (2017). source

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    Premisecitation

    Glutamate supplementation during glutamine deprivation cannot rescue impaired cell growth or mitochondrial respiration, indicating that mitochondrial GLS-catalyzed cleavage of the gamma-nitrogen of glutamine is essential for glutaminolysis.

    “Although glutamate is the major downstream product of glutamine, glutamate supplementation during glutamine deprivation cannot rescue the impaired cell growth or mitochondrial respiration16,43–45, indicating that mitochondrial GLS-catalyzed cleavage of the gamma-nitrogen of glutamine is essential for glutaminolysis.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [16] Yoo, H. C. et al. A variant of SLC1A5 is a mitochondrial glutamine transporter for metabolic reprogramming in cancer cells. Cell Metab. 31, 267–283 (2020). source

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    • cites [43] Zhang, J. et al. Asparagine plays a critical role in regulating cellular adaptation to glutamine depletion. Mol. Cell 56, 205–218 (2014). source

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    • cites [44] Huang, H. et al. Role of glutamine and interlinked asparagine metabolism in vessel formation. Embo J. 36, 2334–2352 (2017). source

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    • cites [45] Pavlova, N. N. et al. As extracellular glutamine levels decline, asparagine becomes an essential amino acid. Cell Metab. 27, 428 (2018). source

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    Premisecitation

    Cytosolic glutamine supports nucleotide biosynthesis, which is essential for rapidly proliferating cells.

    “Cytosolic glutamine supports nucleotide biosynthesis, which is essential for rapidly proliferating cells30.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] Tong, X., Zhao, F. & Thompson, C. B. The molecular determinants of de novo nucleotide biosynthesis in cancer cells. Curr. Opin. Genet. Dev. 19, 32–37 (2009). source

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    Premisenone given

    Glutamine-derived carbon is an important substrate that supports the TCA cycle and the synthesis of glutathione.

    “Glutamine-derived carbon is an important substrate that supports the TCA cycle and the synthesis of glutathione.”
    Quote in the paperSubstantial claim

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    Interpretationcitation

    In cancer cells, the use of glutamate-derived nitrogen for NEAA production may be favored to preserve nitrogen for anabolic reactions and may prevent apoptosis induced by ATF4 activation upon glutamine deprivation.

    “In cancer cells, the use of glutamate-derived nitrogen for NEAA production may be favored in various types of cancer cells to preserve nitrogen for anabolic reactions48 and may prevent apoptosis induced by ATF4 activation upon glutamine deprivation6.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [48] Coloff, J. L. et al. Differential glutamate metabolism in proliferating and quiescent mammary epithelial cells. Cell Metab. 23, 867–880 (2016). source

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    • cites [6] Qing, G. et al. ATF4 regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation. Cancer Cell 22, 631–644 (2012). source

      Not checked in the free run.

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    Premisecitation

    In purine biosynthesis, two glutamines are used to generate IMP, and one glutamine molecule is needed for conversion of IMP to GMP.

    “In purine biosynthesis, two glutamines are used to generate inosine monophosphate (IMP), a precursor of both adenosine monophosphate (AMP) and guanosine monophosphate (GMP). Then, one glutamine molecule is needed for the conversion of IMP to GMP31.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Moffatt, B. A. & Ashihara, H. Purine and pyrimidine nucleotide synthesis and metabolism. Arabidopsis Book 1, e0018 (2002). source

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    Premisecitation

    Mitochondrial α-KG can participate in the TCA cycle, supporting the oxidative phosphorylation pathway or the reductive carboxylation pathway.

    “Mitochondrial α-KG can then participate in the TCA cycle, supporting the oxidative phosphorylation (OXPHOS) pathway or the reductive carboxylation pathway23.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Yang, L. F., Venneti, S. & Nagrath, D. Glutaminolysis: a hallmark of cancer metabolism. Annu. Rev. Biomed. Eng. 19, 163–194 (2017). source

      Not checked in the free run.

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    Premisecitation

    The gamma-nitrogen of glutamine is used in five reactions in de novo nucleotide synthesis, and its bioavailability controls de novo biosynthesis of pyrimidines and purines.

    “The gamma-nitrogen of glutamine is used in five reactions in de novo nucleotide synthesis, and its bioavailability controls de novo biosynthesis of pyrimidines and purines (Fig. 2)5.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Zhang, J., Pavlova, N. N. & Thompson, C. B. Cancer cell metabolism: the essential role of the nonessential amino acid, glutamine. Embo J. 36, 1302–1315 (2017). source

      Not checked in the free run.

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    Premisecitation

    In pyrimidine biosynthesis, one glutamine molecule is consumed by CPS, and one more glutamine molecule is used to synthesize CTP from UTP.

    “In pyrimidine biosynthesis, one glutamine molecule is consumed by a carbamoyl phosphate synthetase enzyme (CPS1 or CPS2, which are localized in the mitochondria and cytosol, respectively). One more glutamine molecule is used to synthesize cytidine triphosphate (CTP) from uridine triphosphate (UTP)31.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Moffatt, B. A. & Ashihara, H. Purine and pyrimidine nucleotide synthesis and metabolism. Arabidopsis Book 1, e0018 (2002). source

      Not checked in the free run.

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    Premisecitation

    Asparagine supplementation enhances expression of GLUL and increases intracellular glutamine usage via glutaminolysis, resulting in recovery of global protein translation blocked by glutamine deprivation.

    “Instead, asparagine supplementation enhances the expression of glutamine synthetase (GLUL) and increases intracellular glutamine usage via glutaminolysis, resulting in the recovery of global protein translation that is blocked by glutamine deprivation45.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45] Pavlova, N. N. et al. As extracellular glutamine levels decline, asparagine becomes an essential amino acid. Cell Metab. 27, 428 (2018). source

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    Premisecitation

    In cells with NRF2 activation, most glutamate is secreted, and cystine is imported by the SLC7A11 (xCT) antiporter mechanism.

    “In cells with NRF2 activation, most glutamate is secreted, and cystine is imported by the SLC7A11 (xCT) antiporter mechanism47 (Fig. 3).”
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    • cites [47] Sayin, V. I. et al. Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer. eLife 6, e28083 (2017). source

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    Premisecitation

    GLSs have at least three isoforms, GLS1, GLS2, and GAC, all localized in mitochondria.

    “GLSs have at least three isoforms, GLS1, GLS2, and GAC (a splicing isoform of GLS1), all of which were recently reported to be localized in mitochondria18–20.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [18] Wang, J. B. et al. Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell 18, 397–397 (2010). source

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    • cites [19] Li, B. et al. Targeting glutaminase 1 attenuates stemness properties in hepatocellular carcinoma by increasing reactive oxygen species and suppressing Wnt/beta-catenin pathway. EBioMedicine 39, 239–254 (2019). source

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    • cites [20] Lukey, M. J. et al. Liver-type glutaminase GLS2 is a druggable metabolic node in luminal-subtype breast cancer. Cell Rep. 29, 76–88 e77 (2019). source

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    Premisecitation

    Asparagine supplementation does not restore levels of other NEAAs (alanine, proline, and glutamate) or any TCA cycle intermediates (α-KG, malate, and fumarate).

    “This finding is surprising because asparagine supplementation does not restore the levels of other NEAAs (alanine, proline, and glutamate) or any TCA cycle intermediates (α-KG, malate, and fumarate).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] Zhang, J. et al. Asparagine plays a critical role in regulating cellular adaptation to glutamine depletion. Mol. Cell 56, 205–218 (2014). source

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    Premisecitation

    In pancreatic cancer cells, oncogenic K-Ras maintains the nucleotide pool via the MAPK-dependent signaling pathway, leading to MYC upregulation, and MEK inhibitors reduce incorporation of glutamine-derived nitrogen into purine nucleotides.

    “In pancreatic cancer cells, oncogenic K-Ras maintains the nucleotide pool via the MAPK-dependent signaling pathway, leading to MYC upregulation, and the use of MEK inhibitors reduces the incorporation of glutamine-derived nitrogen into purine nucleotides38.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Santana-Codina, N. et al. Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis. Nat. Commun. 9, 4945 (2018). source

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    Premisecitation

    PPAT transfers glutamine-derived nitrogen to PRPP, and this step is considered the initial step in purine biosynthesis.

    “PPAT transfers glutamine-derived nitrogen to 5-phosphoribosyl pyrophosphate (PRPP), and this step is considered the initial step in purine biosynthesis37.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Lane, A. N. & Fan, T. W. Regulation of mammalian nucleotide metabolism and biosynthesis. Nucleic Acids Res. 43, 2466–2485 (2015). source

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    Premisecitation

    α-KG is exported from mitochondria through SLC25A11 to the cytosol and participates in fatty acid biosynthesis and NADH generation.

    “In addition, α-KG is exported from mitochondria through SLC25A11 to the cytosol21 and then participates in fatty acid biosynthesis and NADH generation22 (Fig. 1).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [21] Stine, Z. E. & Dang, C. V. Glutamine skipping the Q into mitochondria. Trends Mol. Med. 26, 6–7 (2020). source

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    • cites [22] Mullen, A. R. et al. Oxidation of alpha-ketoglutarate is required for reductive carboxylation in cancer cells with mitochondrial defects. Cell Rep. 7, 1679–1690 (2014). source

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    Premisecitation

    IDH1-dependent reductive glutamine metabolism produces NADPH, which decreases mitochondrial ROS during anchorage-independent growth.

    “In addition, IDH1-dependent reductive glutamine metabolism produces NADPH, which decreases mitochondrial ROS during anchorage-independent growth64.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Jiang, L. et al. Reductive carboxylation supports redox homeostasis during anchorage-independent growth. Nature 532, 255–258 (2016). source

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    Premisecitation

    Extracellular lactate stabilizes HIF-2α, and HIF-2α then transactivates MYC, increasing levels of glutamine transporters and GLS1, resulting in increased glutamine catabolism.

    “In addition, extracellular lactate stabilizes HIF-2α, and HIF-2α then transactivates MYC, increasing the levels of glutamine transporters and GLS1, in turn resulting in increased glutamine catabolism72.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] Perez-Escuredo, J. et al. Lactate promotes glutamine uptake and metabolism in oxidative cancer cells. Cell Cycle 15, 72–83 (2016). source

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    Premisecitation

    Glutamine starvation is associated with impaired uptake of cystine through xCT and decreased intracellular glutathione levels.

    “Consistent with this observation, glutamine starvation has been associated with impaired uptake of cystine through xCT and decreased intracellular glutathione levels62.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [62] Timmerman, L. A. et al. Glutamine sensitivity analysis identifies the xCT antiporter as a common triple-negative breast tumor therapeutic target. Cancer Cell 24, 450–465 (2013). source

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    Premisecitation

    Hypoxia-induced expression of the SLC1A5 variant is mediated by HIF-2α and leads to metabolic reprogramming toward glutamine metabolism in pancreatic cancer cells.

    “Recently, hypoxia-induced expression of the SLC1A5 variant was shown to be mediated by HIF-2α and to lead to metabolic reprogramming toward glutamine metabolism in pancreatic cancer cells16.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Yoo, H. C. et al. A variant of SLC1A5 is a mitochondrial glutamine transporter for metabolic reprogramming in cancer cells. Cell Metab. 31, 267–283 (2020). source

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    Premisecitation

    Cancer cells are under increased oxidative stress caused by oncogenic transformation, leading to metabolic alterations that result in ROS production.

    “Recent studies suggest that cancer cells are under increased oxidative stress caused by oncogenic transformation, leading to metabolic alterations that result in ROS production56.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] Gorrini, C., Harris, I. S. & Mak, T. W. Modulation of oxidative stress as an anticancer strategy. Nat. Rev. Drug Discov. 12, 931–947 (2013). source

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    Premisecitation

    HIF-2α is an important transcription factor in cancer progression and leads to poor prognosis.

    “Given that HIF-2α is an important transcription factor in cancer progression and leads to poor prognosis69,70”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [69] Zhao, J., Du, F., Shen, G., Zheng, F. & Xu, B. The role of hypoxia-inducible factor-2 in digestive system cancers. Cell Death Dis. 6, e1600 (2015). source

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    • cites [70] Li, Z. et al. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell 15, 501–513 (2009). source

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    Premisecitation

    A low level of reactive oxygen species activates tumorigenic growth signaling; when the level exceeds cellular redox capacity, ROS can damage macromolecules such as proteins, lipids and nucleotides.

    “A low level of reactive oxygen species (ROS) activates tumorigenic growth signaling; however, when the level exceeds the cellular redox capacity, ROS can damage macromolecules such as proteins, lipids and nucleotides55.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Weinberg, F. et al. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc. Natl Acad. Sci. USA 107, 8788–8793 (2010). source

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    Premisecitation

    Hypoxia increases dCTP level through the pentose phosphate pathway via glucose metabolism and results in resistance to gemcitabine, a dCTP analog.

    “Hypoxia increases the deoxycytidine triphosphate (dCTP) level through the pentose phosphate pathway (PPP) via glucose metabolism and results in resistance to gemcitabine, a dCTP analog87.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [87] Shukla, S. K. et al. MUC1 and HIF-1alpha signaling crosstalk induces anabolic glucose metabolism to impart gemcitabine resistance to pancreatic cancer. Cancer Cell 32, 392 (2017). source

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    Premisecitation

    HIF-2α represses transcription of CPT1A, which is responsible for mitochondrial β-oxidation by transporting fatty acids, and results in lipid deposition.

    “Furthermore, HIF-2α represses the transcription of carnitine palmitoyltransferase 1A (CPT1A), which is responsible for mitochondrial β-oxidation by transporting fatty acids and results in lipid deposition78.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [78] Du, W. et al. HIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism. Nat. Commun. 8, 1769 (2017). source

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    Premisecitation

    Asparagine functions as an exchange factor needed for uptake of other amino acids required for mTORC1 activation and for enhanced nucleotide biosynthesis under mitochondrial electron transport chain impairment.

    “Recently, asparagine has been reported to function as an exchange factor needed for the uptake of other amino acids that are required for mTORC1 activation53 and for enhanced nucleotide biosynthesis under mitochondrial electron chain transport system impairment54.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [53] Krall, A. S., Xu, S., Graeber, T. G., Braas, D. & Christofk, H. R. Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor. Nat. Commun. 7, 11457 (2016). source

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    • cites [54] Krall, A. S. et al. Asparagine signals mitochondrial respiration and can be targeted to impair tumour growth. bioRxiv, 2020.2003.2017.995670 (2020). source

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    Premisecitation

    l-asparaginase treatment alone can reduce the incidence of breast cancer metastasis to the lung without affecting primary tumor growth.

    “This study suggested that l-asparaginase treatment alone can reduce the incidence of breast cancer metastasis to the lung without affecting primary tumor growth.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] Knott, S. R. V. et al. Asparagine bioavailability governs metastasis in a model of breast cancer. Nature https://doi.org/10.1038/nature26162 (2018). source

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    Interpretationreasoning

    Glutamine maintains cellular redox homeostasis by supplying fuels for glutathione synthesis and endowing reducing power in the form of NADPH for sustaining tumor growth.

    “In summary, glutamine maintains cellular redox homeostasis by supplying fuels for glutathione synthesis and endowing reducing power in the form of NADPH for sustaining tumor growth.”
    Quote in the paperSubstantial claim

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    Premisereasoning

    This mechanism is very important in clear cell renal cell carcinoma (ccRCC) in which HIF-2α signaling is constitutively activated and intracellular lipid droplets are abundant.

    “This mechanism is very important in clear cell renal cell carcinoma (ccRCC) in which HIF-2α signaling is constitutively activated and intracellular lipid droplets are abundant.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Cells in several types of cancers are characterized by significant enhancement of glutathione biosynthesis, and this metabolic vulnerability has been targeted to sensitize these cancer cells to ROS-induced drugs.

    “Furthermore, cells in several types of cancers are characterized by significant enhancement of glutathione biosynthesis, and this metabolic vulnerability has been targeted to sensitize these cancer cells to ROS-induced drugs63.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] Okazaki, K., Papagiannakopoulos, T. & Motohashi, H. Metabolic features of cancer cells in NRF2 addiction status. Biophys. Rev. https://doi.org/10.1007/s12551-020-00659-8 (2020). source

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  • May combine two claims.

    Premisecitation

    Glutamine is a direct fuel for glutathione as a source of glutamate and is indirectly responsible for cystine uptake via the xCT antiporter system, which takes up cystine and simultaneously secretes glutamate.

    “As shown in Fig. 3, glutamine is a direct fuel for the use of glutathione as a source of glutamate and is indirectly responsible for cystine uptake via the xCT antiporter system, which takes up cystine and simultaneously secretes glutamate61.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] Muir, A. et al. Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition. eLife https://doi.org/10.7554/eLife.27713 (2017). source

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  • May combine two claims.

    Premisecitation

    HIF-2α can be targeted by selective inhibitors, and these molecules effectively suppress cancer cell growth and tumor angiogenesis characteristics in ccRCC.

    “Indeed, recent studies have shown that HIF-2α can be targeted by selective inhibitors and have indicated that these molecules effectively suppress cancer cell growth and tumor angiogenesis characteristics in ccRCC79–82.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [79] Scheuermann, T. H. et al. Allosteric inhibition of hypoxia inducible factor-2 with small molecules. Nat. Chem. Biol. 9, 271–276 (2013). source

      Not checked in the free run.

    • cites [80] Wallace, E. M. et al. A small-molecule antagonist of HIF2alpha Is efficacious in preclinical models of renal cell carcinoma. Cancer Res. 76, 5491–5500 (2016). source

      Not checked in the free run.

    • cites [81] Chen, W. et al. Targeting renal cell carcinoma with a HIF-2 antagonist. Nature 539, 112–117 (2016). source

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    • cites [82] Cho, H. et al. On-target efficacy of a HIF-2alpha antagonist in preclinical kidney cancer models. Nature 539, 107–111 (2016). source

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  • May combine two claims.

    Premisecitation

    HIF-1α is activated due to blockade of its degradation pathway mediated by low oxygen levels, thereby increasing expression of target genes including glycolytic enzymes and glucose transporters, and increasing lactate secretion.

    “HIF-1α is activated due to blockade of its degradation pathway mediated by low oxygen levels, thereby increasing the expression of target genes, including those encoding glycolytic enzymes and glucose transporters, and increasing lactate secretion67.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] Denko, N. C. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat. Rev. Cancer 8, 705–713 (2008). source

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  • May combine two claims.

    Premisecitation

    Acidic pH impairs activity of the mitochondrial L-2-HG removal enzyme L2HGDH and enhances protein stabilization of HIF-1α, leading to its escape from the degradation pathway.

    “Acidic pH impairs the activity of the mitochondrial L-2-HG removal enzyme L-2-hydroxyglutarate dehydrogenase (L2HGDH) and enhances the protein stabilization of HIF-1α, leading to its escape from the degradation pathway90.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [90] Nadtochiy, S. M. et al. Acidic pH is a metabolic switch for 2-hydroxyglutarate generation and signaling. J. Biol. Chem. 291, 20188–20197 (2016). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    L-2-HGA is an autosomal recessive encephalopathy with onset in childhood that causes developmental delays, epilepsy and cerebellar ataxia.

    “L-2-HGA is an autosomal recessive encephalopathy with an onset in childhood that causes developmental delays, epilepsy and cerebellar ataxia, the traditional clinical signs of this condition.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [92] Kranendijk, M., Struys, E. A., Salomons, G. S., Van der Knaap, M. S. & Jakobs, C. Progress in understanding 2-hydroxyglutaric acidurias. J. Inherit. Metab. Dis. 35, 571–587 (2012). source

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  • May combine two claims.

    Premisecitation

    In IDH1/2 mutant cells, glutamine flux is directed toward R-2-HG generation, with kinetics similar to glutamate or α-KG formation via glutaminolysis.

    “In this study, glutamine flux was directed toward the generation of R-2-HG in IDH1/2 mutant cells, and the kinetics of R-2-HG formation were proportionally of the same order of magnitude as those of glutamate or α-KG formation via glutaminolysis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [121] Salamanca-Cardona, L. et al. In vivo imaging of glutamine metabolism to the oncometabolite 2-hydroxyglutarate in IDH1/2 mutant tumors. Cell Metab. 26, 830–841 e833 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the obese state, glutamine metabolism is impaired, leading to increased chromatin O-GlcNAcylation and activation of genes in proinflammatory pathways.

    “The researchers discovered that glutamine metabolism is impaired in the obese state, leading to increased chromatin O-GlcNAcylation and activation of genes in proinflammatory pathways.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [110] Petrus, P. et al. Glutamine links obesity to inflammation in human white adipose tissue. Cell Metab. 31, 375 (2020). source

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  • May combine two claims.

    Premisecitation

    While NRF2 induces chemoresistance in KRAS-driven cancers, suppressing glutamine metabolism leads to weakened chemoresistance in these cancer cells.

    “Consistent with these findings, while NRF2 induces chemoresistance in KRAS-driven cancers, suppressing glutamine metabolism leads to weakened chemoresistance in these cancer cells85.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85] Mukhopadhyay, S. et al. Undermining glutaminolysis bolsters chemotherapy while NRF2 promotes chemoresistance in KRAS-driven pancreatic cancers. Cancer Res. https://doi.org/10.1158/0008-5472.CAN-19-1363 (2020). source

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  • May combine two claims.

    Premisecitation

    Mutations in succinate dehydrogenase subunit B (SDHB) cause susceptibility to familial pheochromocytoma, familial paraganglioma, and gastrointestinal stromal tumors.

    “In cancer cells, mutations in succinate dehydrogenase subunit B (SDHB) cause susceptibility to familial pheochromocytoma99 and familial paraganglioma100 as well as gastrointestinal stromal tumors101.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [99] Astuti, D. et al. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am. J. Hum. Genet. 69, 640–640 (2001). source

      Not checked in the free run.

    • cites [100] Letouze, E. et al. SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell 23, 739–752 (2013). source

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    • cites [101] Janeway, K. A. et al. Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc. Natl Acad. Sci. USA 108, 314–318 (2011). source

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  • May combine two claims.

    Premisecitation

    At later stages of pluripotency, α-KG derived from glutamine can promote early differentiation, suggesting that the stage of cellular maturity can alter the effect of α-KG.

    “In addition, at later stages of pluripotency, α-KG derived from glutamine can promote early differentiation, suggesting that the stage of cellular maturity can alter the effect of α-KG105.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [105] TeSlaa, T. et al. alpha-Ketoglutarate accelerates the initial differentiation of primed human pluripotent stem cells. Cell Metab. 24, 485–493 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SDH mutation was discovered in paraganglioma and pheochromocytoma, and later in gastrointestinal, neuroblastoma, renal, thyroid, and testicular tumors.

    “In 2008, mutation of SDH was discovered in cancers such as paraganglioma and pheochromocytoma cells124. Later, similar observations were made in gastrointestinal tumors, neuroblastomas, renal tumors, thyroid tumors, and testicular tumors125,126.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [124] Richter, S. et al. Krebs cycle metabolite profiling for identification and stratification of pheochromocytomas/paragangliomas due to succinate dehydrogenase deficiency. J. Clin. Endocrinol. Metab. 99, 3903–3911 (2014). source

      Not checked in the free run.

    • cites [125] Bardella, C., Pollard, P. J. & Tomlinson, I. SDH mutations in cancer. Biochim Biophys. Acta 1807, 1432–1443 (2011). source

      Not checked in the free run.

    • cites [126] Müller, S. N. U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat. Genet. 26, 268–270 (2000). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Under normal physiological conditions, LDHA catalyzes the conversion of pyruvate to lactate; under hypoxic conditions, LDHA can produce L-2-HG.

    “Under normal physiological conditions, LDHA catalyzes the conversion of pyruvate to lactate. However, under hypoxic conditions, LDHA can produce L-2-HG.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In these reactions, α-KG is oxidized to succinate, and increasing levels of succinate can suppress progression of α-KG-dependent histone or DNA demethylase reactions.

    “In these reactions, α-KG is oxidized to succinate, and increasing levels of succinate can suppress the progression of α-KG-dependent histone or DNA demethylase reactions98.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [98] Schvartzman, J. M., Thompson, C. B. & Finley, L. W. S. Metabolic regulation of chromatin modifications and gene expression. J. Cell Biol. 217, 2247–2259 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Glutamine-derived R-2-HG accumulates and prevents differentiation of myeloblasts, resulting in uncontrolled growth of blood cells.

    “Indeed, glutamine-derived R-2-HG accumulates and prevents the differentiation of myeloblasts, resulting in uncontrolled growth of blood cells122.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [122] Gonsalves, W. I. et al. Glutamine-derived 2-hydroxyglutarate is associated with disease progression in plasma cell malignancies. JCI Insight https://doi.org/10.1172/jci.insight.94543 (2018). source

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  • May combine two claims.

    Premisecitation

    SDH-deficient cells exhibit increased tumorigenesis, reversed by α-KG, supporting that succinate accumulation contributes to tumorigenesis through epigenetic modification.

    “Several studies have shown that SDH-deficient cells exhibit increased tumorigenesis and that this increase is reversed by the addition of α-KG, supporting the idea that succinate accumulation contributes to tumorigenesis through epigenetic modification100.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [100] Letouze, E. et al. SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell 23, 739–752 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    An increased ratio of succinate to α-KG in cancers resulting from impaired SDH activity is related to pervasive DNA hypermethylation, which contributes to downregulation of key genes implicated in cell differentiation and cancer stages.

    “An increased ratio of succinate to α-KG in cancers resulting from impaired succinate dehydrogenase (SDH) activity is related to pervasive DNA hypermethylation, which contributes to the downregulation of key genes implicated in cell differentiation and cancer stages102.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] Killian, J. K. et al. Succinate dehydrogenase mutation underlies global epigenomic divergence in gastrointestinal stromal tumor. Cancer Discov. 3, 648–657 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    These hydroxylation reactions require Fe2+ as a cofactor, O2 as a cosubstrate and ascorbic acid as a reductase.

    “These hydroxylation reactions also require Fe2+ as a cofactor, O2 as a cosubstrate and ascorbic acid (vitamin C) as a reductase, which restore the activity of 2-OGDD enzymes (Fig. 5a).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In T cell activation, glutamine deprivation alters activation of naive CD4+ T cells and results in their differentiation into Foxp3+ regulatory T cells, which have suppressor functions.

    “In T cell activation, glutamine deprivation has been shown to alter the activation of naive CD4+ T cells and result in their differentiation into forkhead box P3-positive (Foxp3+) regulatory T (Treg) cells, which have suppressor functions109.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] Klysz, D. et al. Glutamine-dependent alpha-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation. Sci. Signal. 8, ra97 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    L-2-HG has an oncogenic effect and is associated with tumorigenesis under hypoxic conditions.

    “These studies indicate an oncogenic effect of L-2-HG and the association of L-2-HG with tumorigenesis under hypoxic conditions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    R-2-HG inhibits α-KG-dependent dioxygenases and demethylases.

    “The role of R-2-HG as an oncometabolite has been implicated in epigenetic modifications through the inhibition of α-KG-dependent dioxygenases and demethylases”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [117] Figueroa, M. E. et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553–567 (2010). source

      Not checked in the free run.

    • cites [118] Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012). source

      Not checked in the free run.

    • The authors state this as an assumption: R-2-HG inhibition of α-KG-dependent dioxygenases and demethylases is a driver of tumorigenesis.

  • May combine two claims.

    Interpretationreasoning

    These events mitigate cellular reductive stress by suppressing key metabolic pathways, indicating a crucial role of L-2-HG.

    “These events mitigate cellular reductive stress by suppressing key metabolic pathways, indicating a crucial role of L-2-HG.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Severe glutamine deprivation in the core region of solid tumors leads to dramatic histone hypermethylation due to decreased α-KG levels and decreased activity of Jumonji domain-containing histone demethylases, resulting in cancer cell dedifferentiation and resistance to BRAF inhibitors.

    “This severe glutamine deprivation leads to dramatic histone hypermethylation due to decreased α-KG levels subsequent to decreased activity of Jumonji domain-containing histone demethylases and results in cancer cell dedifferentiation and resistance to BRAF inhibitors103.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [103] Pan, M. et al. Regional glutamine deficiency in tumours promotes dedifferentiation through inhibition of histone demethylation. Nat. Cell Biol. 18, 1090–1101 (2016). source

      Not checked in the free run.

    • Rests on an assumption: The core region of solid tumors exhibits a deficiency of glutamine compared with other amino acids.

  • May combine two claims.

    Premisecitation

    GLS1 knockdown significantly suppresses NADH and ATP production in cancer cells, so glutamate and α-KG supply for MAS activity is critical for ATP production in cancer cells.

    “Glutamate and α-KG serve as important exchangers in the MAS, and since GLS1 knockdown significantly suppresses NADH and ATP production in cancer cells143, the supply of glutamate and α-KG for the induction of MAS activity is evidently critical for ATP production in cancer cells”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [143] Lee, J. S. et al. Dual targeting of glutaminase 1 and thymidylate synthase elicits death synergistically in NSCLC. Cell Death Dis. 7, e2511 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Facilitation of glutaminolysis leads to accumulation of excess ammonia, and high ammonia is a potent inducer of autophagy.

    “Hence, the facilitation of glutaminolysis leads to the accumulation of excess ammonia within cells, and a high concentration of ammonia is a potent inducer of autophagy167”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [167] Eng, C. H., Yu, K., Lucas, J., White, E. & Abraham, R. T. Ammonia derived from glutaminolysis is a diffusible regulator of autophagy. Sci. Signal. 3, ra31 (2010).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Upon glutamine starvation, p53 activity is induced and can help cancer cells adapt to nutrient starvation.

    “Upon glutamine starvation, p53 activity is induced and can help cancer cells adapt to nutrient starvation through diverse mechanisms148.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [148] Reid, M. A. et al. The B55alpha subunit of PP2A drives a p53-dependent metabolic adaptation to glutamine deprivation. Mol. Cell 50, 200–211 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High fumarate inhibits TET enzymes, stimulating EMT and leading to cancer metastasis.

    “In addition, fumarate inhibits TET enzymes, which stimulate EMT, leading to cancer metastasis131,132.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [131] Sciacovelli, M. et al. Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Nature 537, 544–547 (2016). source

      Not checked in the free run.

    • cites [132] Laukka, T. et al. Fumarate and succinate regulate expression of hypoxia-inducible genes via TET enzymes. J. Biol. Chem. 291, 4256–4265 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    mTORC1 activation via glutaminolysis suppresses autophagy and the DNA damage response.

    “In addition, mTORC1 activation via glutaminolysis suppresses autophagy and the DNA damage response164,165.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [164] Sanli, T., Steinberg, G. R., Singh, G. & Tsakiridis, T. AMP-activated protein kinase (AMPK) beyond metabolism: a novel genomic stress sensor participating in the DNA damage response pathway. Cancer Biol. Ther. 15, 156–169 (2014). source

      Not checked in the free run.

    • cites [165] Shen, C. & Houghton, P. J. The mTOR pathway negatively controls ATM by upregulating miRNAs. Proc. Natl Acad. Sci. USA 110, 11869–11874 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Autophagy suppresses anoikis and promotes metastasis.

    “Specifically, autophagy suppresses anoikis induced by the detachment of cancer cells from the extracellular matrix (ECM) and hence promotes metastasis169.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [169] Debnath, J. Detachment-induced autophagy during anoikis and lumen formation in epithelial acini. Autophagy 4, 351–353 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Glutamine metabolism plays a critical role in tumor progression by supporting mitochondrial oxidative phosphorylation, supplying TCA cycle intermediates, glutathione synthesis, NEAA synthesis, and producing NADPH.

    “Unsurprisingly, glutamine metabolism plays a critical role in tumor progression since it not only supports mitochondrial oxidative phosphorylation but also supplies metabolic intermediates for the TCA cycle, glutathione synthesis, and NEAA synthesis and simultaneously produces NADPH157–159.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [157] Szeliga, M. & Obara-Michlewska, M. Glutamine in neoplastic cells: focus on the expression and roles of glutaminases. Neurochem. Int. 55, 71–75 (2009). source

      Not checked in the free run.

    • cites [158] Eng, C. H. & Abraham, R. T. Glutaminolysis yields a metabolic by-product that stimulates autophagy. Autophagy 6, 968–970 (2010). source

      Not checked in the free run.

    • cites [159] Rabinowitz, J. D. & White, E. Autophagy and metabolism. Science 330, 1344–1348 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High mTORC1 activity in cancer cells promotes aerobic glycolysis and drives glucose addiction.

    “Accordingly, high mTORC1 activity in cancer cells promotes aerobic glycolysis and drives glucose addiction162,163”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [162] Poulain, L. et al. High mTORC1 activity drives glycolysis addiction and sensitivity to G6PD inhibition in acute myeloid leukemia cells. Leukemia 31, 2326–2335 (2017). source

      Not checked in the free run.

    • cites [163] Dutchak, P. A. et al. Loss of a negative regulator of mTORC1 induces aerobic glycolysis and altered fiber composition in skeletal muscle. Cell Rep. 23, 1907–1914 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Glutaminolysis can suppress autophagy via mTORC1 but stimulate autophagy via excess ammonia.

    “Therefore, glutaminolysis can suppress autophagy by activating the mTORC1 pathway but, on the other hand, can stimulate autophagy in the context of excess ammonia production.”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    Succinate supports tumorigenesis through inhibition of PHD, stabilizing HIF-1α and maintaining metabolic reprogramming.

    “The other mechanism by which succinate supports tumorigenesis acts through the inhibition of hypoxia-inducible factor prolyl hydroxylase (PHD). PHD activates the pseudohypoxic response by stabilizing HIF-1α, which is a well-known tumorigenesis enhancer”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [127] Selak, M. A. et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 7, 77–85 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cancer cells driven by oncogenic MYC, K-Ras, and PIK3CA require glutamine for survival and display extensive anabolic utilization of glutamine.

    “Notably, cancer cells driven by oncogenic MYC, K-Ras, and PIK3CA require glutamine for their survival and display extensive anabolic utilization of glutamine29,174,175”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [29] Son, J. et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature https://doi.org/10.1038/nature12317 (2013). source

      Not checked in the free run.

    • cites [174] Dang, C. V. Rethinking the Warburg effect with Myc micromanaging glutamine metabolism. Cancer Res. 70, 859–862 (2010). source

      Not checked in the free run.

    • cites [175] Hao, Y. et al. Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer. Nat. Commun. 7, 11971 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Enhanced glutaminolysis might contribute to cancer initiation and progression by stimulating cell growth via mTORC1 and aerobic glycolysis while inhibiting autophagy and the DNA damage response.

    “Therefore, enhanced glutaminolysis might eventually contribute to the initiation and progression of cancer by stimulating cell growth via the mTORC1 pathway and enhancing aerobic glycolysis while disrupting the proper elimination of misfolded proteins, damaged DNA and organelles through the inhibition of autophagy and the DNA damage response166.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [166] Villar, V. H., Merhi, F., Djavaheri-Mergny, M. & Duran, R. V. Glutaminolysis and autophagy in cancer. Autophagy 11, 1198–1208 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Cancer glutamine metabolism shows extraordinary flexibility and is intertwined with diverse metabolic pathways.

    “Collectively, cancer glutamine metabolism shows extraordinary flexibility and is intertwined with diverse metabolic pathways.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    During the DNA damage response, normal cells show decreased glutaminolysis controlled by SIRT4 suppressing GLUD1; absence of SIRT4 causes delayed DNA repair and chromosomal instability, suggesting a tumor suppressor effect.

    “Moreover, evidence has shown that during the DNA damage response, normal cells show a decrease in glutaminolysis controlled by SIRT4 protein suppressing GLUD1. In the absence of SIRT4, a failure to undergo cell cycle arrest induced by DNA damage causes a delay in DNA repair and increased chromosomal instability, suggesting a tumor suppressor effect of SIRT4151.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [151] Jeong, S. M. et al. SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism. Cancer Cell 23, 450–463 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Under DNA damage such as radiation, glutamine is conditionally essential to support nucleotide synthesis and redox homeostasis; radioresistant cancer cells reprogram flux toward glutamine anabolism and express glutamine synthetase.

    “Under DNA damage such as radiation, glutamine is conditionally essential to support the synthesis of nucleotides and redox homeostasis. It has recently been demonstrated that radioresistant cancer cells reprogram metabolic flux toward glutamine anabolism. Under these conditions, cancer cells highly express glutamine synthetase, facilitating cancer cell growth under radiation stress150.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [150] Fu, S. J. et al. Glutamine synthetase promotes radiation resistance via facilitating nucleotide metabolism and subsequent DNA damage repair. Cell Rep. 28, 1136 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Glutaminolysis can reinforce metabolic reprogramming, implying glutamine metabolism plays a crucial role in tumorigenesis and tumor progression.

    “Intriguingly, this study regarding elevated glutamine metabolism in cancer cells also showed that glutaminolysis could in turn reinforce metabolic reprogramming, thus implying that glutamine metabolism plays a crucial role in tumorigenesis and tumor progression16”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Yoo, H. C. et al. A variant of SLC1A5 is a mitochondrial glutamine transporter for metabolic reprogramming in cancer cells. Cell Metab. 31, 267–283 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mitochondrial glutamine transporter level controls cellular ATP level stimulated by glutamine, suggesting glutamine is an important energy source via mitochondrial glutaminolysis.

    “Additionally, the level of the mitochondrial glutamine transporter controls the cellular ATP level stimulated by glutamine, suggesting that glutamine is an important energy source via mitochondrial glutaminolysis16.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Yoo, H. C. et al. A variant of SLC1A5 is a mitochondrial glutamine transporter for metabolic reprogramming in cancer cells. Cell Metab. 31, 267–283 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fumarate hydratase inactivation mutation was discovered in renal cell cancer and leads to fumarate accumulation in skin cancer, uterine leiomyomas, breast, bladder, and Leydig cell tumors.

    “In 2001, mutation of fumarate hydratase leading to its inactivation was discovered in renal cell cancer129. Mutation of this enzyme leads to fumarate accumulation not only in skin cancer and uterine leiomyomas but also in breast, bladder, and Leydig cell tumors130.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [129] Virpi Launonen, O. V. et al. Inherited susceptibility to uterine leiomyomas and renal cell cancer. PNAS 98, 3387–3392 (2001). source

      Not checked in the free run.

    • cites [130] Tomlinson, I. P. et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat. Genet. 30, 406–410 (2002). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Metabolic reliance on glutamine arises via the intrinsic functional diversity of glutamine, supporting macromolecule biosynthesis and reinforcing the TCA cycle.

    “In conclusion, metabolic reliance on glutamine arises via the intrinsic functional diversity of glutamine, supporting macromolecule biosynthesis and reinforcing the TCA cycle.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Human glioblastoma cells do not rely much on circulating glutamine for proliferation but more on glutamate to synthesize glutamine via glutamine synthetase to fuel purine biosynthesis.

    “Furthermore, human glioblastoma cells do not rely much on circulating glutamine for proliferation but rather more on glutamate to synthesize glutamine via glutamine synthetase to fuel purine biosynthesis193.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [193] Tardito, S. et al. Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma. Nat. Cell Biol. 17, 1556–1568 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    K-Ras sensitizes cells to glutamine deprivation, and K-Ras knockdown rescues cells from apoptosis induced by low glutamine.

    “Consistent with this observation, K-Ras sensitizes cells to glutamine deprivation, and K-Ras knockdown rescues cells from apoptosis induced by low glutamine levels187.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [187] Gwinn, D. M. et al. Oncogenic KRAS regulates amino acid homeostasis and asparagine biosynthesis via ATF4 and alters sensitivity to L-asparaginase. Cancer Cell 33, 91–107 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Blocking glutamine metabolism through JHU083 suppressed tumor cell metabolism and mitigated the tumor microenvironment, unleashing an antitumor T cell response.

    “The researchers showed that blocking glutamine metabolism through JHU083 not only suppressed tumor cell metabolism but also mitigated the tumor microenvironment, which is hostile to the immune response due to its hypoxic, acidic, and nutrient-depleted conditions, unleashing the natural antitumor T cell response.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [200] Leone, R. D. et al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science 366, 1013 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    In tumorigenesis, glutamine-derived 2-HG alters the epigenetic landscape of chromosomes and induces oncogenic transformation.

    “In the context of tumorigenesis, glutamine-derived 2-HG alters the epigenetic landscape of chromosomes and induces oncogenic transformation.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: R-2-HG inhibition of α-KG-dependent dioxygenases and demethylases is a driver of tumorigenesis.

  • May combine two claims.

    Premisecitation

    Glutaminolysis increases α-KG, resulting in GTP loading of RagB and lysosomal translocation of mTORC1 in human cancer cell lines.

    “According to another study, glutaminolysis increases the level of α-KG production, resulting in GTP loading of RagB and lysosomal translocation of the mTORC1 complex in human cancer cell lines160.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [160] Duran, R. V. & Hall, M. N. Glutaminolysis feeds mTORC1. Cell Cycle 11, 4107–4108 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Concurrent JHU083 and anti-PD-1 improved antitumor effects compared with anti-PD-1 alone, suggesting metabolic plasticity between cancer cells and effector T cells.

    “They also confirmed that concurrent treatment with JHU083 and anti-PD-1 checkpoint inhibitor improved the antitumor effects compared with anti-PD-1 treatment alone, suggesting the presence of metabolic plasticity between cancer cells and effector T cells, which could be exploited as a metabolic checkpoint for cancer immunotherapy200.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [200] Leone, R. D. et al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science 366, 1013 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Loss of SIRT4 enhances glutamine-dependent proliferation and genomic instability, contributing to tumorigenesis.

    “Accordingly, loss of SIRT4 enhances glutamine-dependent proliferation and genomic instability, which simultaneously contribute to tumorigenesis151.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [151] Jeong, S. M. et al. SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism. Cancer Cell 23, 450–463 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SLC1A5 is considered the most critical plasma membrane glutamine transporter in cancer cells and has clinical importance.

    “In addition, SLC1A5 was shown to have clinical importance, and it is considered the most critical plasma membrane glutamine transporter in cancer cells201.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [201] Liu, Y. et al. The role of ASCT2 in cancer: a review. Eur. J. Pharm. 837, 81–87 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GLS overexpression is observed in different tumor cells and functions in metabolic reprogramming of glutamine addiction.

    “GLS overexpression has been observed in different tumor cells, and these enzymes are found to function in the metabolic reprogramming of glutamine addiction in cancer198.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [198] Lobo, C. et al. Inhibition of glutaminase expression by antisense mRNA decreases growth and tumourigenicity of tumour cells. Biochem. J. 348, 257–261 (2000). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    SLC1A5 might not be an appropriate target because it is not the only plasma membrane glutamine transporter and its function would be compensated by SLC38A1 and SLC38A2.

    “SLC1A5 might not be an appropriate target for suppressing glutamine uptake by cancer cells because it is not the only plasma membrane glutamine transporter, and its function would therefore be compensated by other redundant glutamine transporters such as SLC38A1 and SLC38A2.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    GPNA also inhibits other glutamine transporters such as SLC38A1, and V-9302 is effective even in SLC1A5 knockout models.

    “However, other researchers have argued that controversial issues exist because GPNA also inhibits other glutamine transporters, such as SLC38A1, and V-9302 is effective even in SLC1A5 knockout models206,207.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [206] Broer, A., Fairweather, S. & Broer, S. Disruption of amino acid homeostasis by novel ASCT2 inhibitors involves multiple targets. Front. Pharm. 9, 785 (2018). source

      Not checked in the free run.

    • cites [207] Chiu, M. et al. GPNA inhibits the sodium-independent transport system L for neutral amino acids. Amino Acids 49, 1365–1372 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CB-839 is the only GLS inhibitor to proceed to clinical trials; its selectivity toward GLS1 and failure to inhibit GLS2 require in-depth study.

    “Among these agents, CB-839 is the only one to proceed to clinical trials; however, its selectivity toward GLS1 and failure to inhibit the compensatory effect of GLS2 require in-depth study14.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Gross, M. I. et al. Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol. Cancer Ther. 13, 890–901 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activation of K-Ras in cancer cells results in bypass of the late G1 glutamine-dependent checkpoint; glutamine deprivation causes growth arrest in S or G2/M instead of G1.

    “Importantly, activation of K-Ras in cancer cells results in bypass of the late G1 glutamine-dependent checkpoint. Specifically, glutamine deprivation in K-Ras-driven cancer cells leads to growth arrest in S or G2/M phase instead of in G1 phase.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [185] Saqcena, M. et al. Blocking anaplerotic entry of glutamine into the TCA cycle sensitizes K-Ras mutant cancer cells to cytotoxic drugs. Oncogene 34, 2672–2680 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Glutamine acts as a precursor for synthesis of NEAAs including asparagine and arginine, implicated in mTORC1 activation.

    “Moreover, glutamine also acts as a precursor for the synthesis of various NEAAs, including asparagine and arginine, implicated in mTORC1 activation39.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Choi, B. H. & Coloff, J. L. The diverse functions of non-essential amino acids in cancer. Cancers 11, 675 (2019). source

      Not checked in the free run.

87 of 87

  • The paper relies on this without support.

    The core region of solid tumors exhibits a deficiency of glutamine compared with other amino acids.

    “Moreover, the core region of solid tumors exhibits a deficiency of glutamine compared with other amino acids.”

  • The authors state this as an assumption.

    R-2-HG inhibition of α-KG-dependent dioxygenases and demethylases is a driver of tumorigenesis.

    “which has been assumed to be a driver of tumorigenesis117,118”

  • The paper relies on this without support.

    Therapeutic effects of targeting glutamine metabolism observed in preclinical cancer models will translate to human cancers.

    “Certain types of cancer, including renal cell carcinoma, hematologic malignancies, glioblastoma, pancreatic cancer, and those reported to depend on HIF-2α, seem to depend on glutamine; hence, targeting glutamine metabolism may show therapeutic effects in these cancers.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Glutamine is a nonessential amino acid primarily produced by glutamine synthetase using glutamate and ammonia as substrates, and it is recognized as a significant regulator of osteoblasts due to the increased demand for amino acids resulting from augmented bone matrix synthesis during bone formation.

    “Glutamine (Gln), a nonessential amino acid (NEAA), is primarily produced by the enzyme Gln synthetase (GS) using glutamate (Glu) and ammonia (NH3) as substrates. It has been recognized as a significant regulator of osteoblasts due to the increased demand for amino acids resulting from the augmented synthesis of the bone matrix during bone formation [61].”

    From Mesenchymal stromal cells in bone marrow niche of patients with multiple myeloma: a double-edged sword (2025) · cites this paper as [61]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • Glutamine is a major nitrogen source for proliferating cells.

    “Glutamine is also a major source of nitrogen for proliferating cells52,54.”

    From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [54]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • PHD inhibition and PHD activity are both said to promote the pseudohypoxic response

    Minor

    The succinate section first says tumorigenesis proceeds through inhibition of PHD, then says PHD itself activates the pseudohypoxic response by stabilizing HIF-1α. These assign the same response to opposing states of PHD.

  • SLC6A14 inhibitor assignment conflicts with Fig. 8

    Minor

    The text assigns erastin to SLC6A14 and α-Me-Trp to SLC7A11, respectively. The Fig. 8 caption instead assigns α-Me-Trp to SLC6A14 and lists erastin as an SLC7A11 inhibitor.

  • Conflicting glutamine counts for conversion of UTP to CTP

    Minor

    The text says one glutamine molecule is needed to convert UTP to CTP, but the Fig. 2 caption says two are spent on that conversion.

  • Two different enzymes are credited with converting succinate to fumarate

    Minor

    The fumarate section attributes production of fumarate from succinate to fumarate hydratase, while the succinate section attributes that conversion to SDH.

  • R-2-HG is said to both activate and inhibit demethylases

    Minor

    The Fig. 5 caption says accumulated R-2-HG ultimately activates TET and JHDM enzymes, whereas the R-2-HG section says its effect is inhibition of dioxygenases and demethylases. This reverses the stated epigenetic mechanism.

5 of 5

Cites

Flagged first, then by citations

Research works printed but not linked: 4

  1. Metallo, C. M. et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481, 380–384 (2011). · DOI · Paper page
  2. Astuti, D. et al. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am. J. Hum. Genet. 69, 49–54 (2001). · DOI · Paper page
  3. Patel, D. et al. Aspartate rescues S-phase arrest caused by suppression of glutamine utilization in KRas-driven cancer cells. J. Biol. Chem. 291, 9322–9329 (2016). · DOI · Paper page
  4. Lobo, C. et al. Inhibition of glutaminase expression by antisense mRNA decreases growth and tumourigenicity of tumour cells. Biochem. J. 348, 257–261 (2000). · DOI · Paper page

Cited by

Sorted by citations

Related

Authors
Yoo, H. C., Yu, Y. C., Sung, Y., & Han, J. M.
Affiliations
Yonsei University (KR)
Corresponding author
Han, Jung Min
ORCID
Venue
Experimental & Molecular Medicine
Publisher
Springer Science and Business Media LLC
Published
2020-09
Volume
52
Issue
9
Pages
1496-1516
ISSN
  • 1226-3613 (ISSN-L)
  • 2092-6413
DOI
10.1038/s12276-020-00504-8
PMC
PMC8080614
OpenAlex
W3087165503
Semantic Scholar
b25e30707323859ba4f4b151172c143c4b727ae6
Cited by
1,021
References
212
Citations by year
2026: 172 · 2025: 258 · 2024: 220 · 2023: 195 · 2022: 127 · 2021: 49
FWCI
9.47
Type
journal article
Language
en
Open access
Licence
Locations
  • Experimental & Molecular Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Research Foundation (2018R1A6A1A03023718)
  • Yonsei University
  • National Research Foundation of Korea (2018R1A6A1A03023718, 2020M3E5E2040282, 2020R1I1A1A01067423)
  • Ministry of Science and ICT, South Korea (2018R1A6A1A03023718)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords
glutamine metabolism, tumor hypoxia, drug resistance, metabolic reprogramming, glutaminolysis, cancer metabolism, glutamine transporter, epigenetic regulation, carcinogenesis, biosynthesis, bioenergetics
MeSH terms
Animals, Cell Transformation, Neoplastic, Disease Susceptibility, Energy Metabolism, Glutamine, Humans, Neoplasms, Oxidation-Reduction, Signal Transduction, Gene Expression Regulation, Neoplastic, Epigenesis, Genetic, Metabolic Networks and Pathways, Metabolomics, Metabolome

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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