Glutamine reliance in cell metabolism

In the paper

“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.”

What the sources say

• Not checked yetcites [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
• Partly supported

  The Results section, “Asparagine Restores Viability, but not Anaplerosis, Other Nonessential Amino Acids, or Proliferation” (page unavailable), reports that glutamate substitution failed to suppress apoptosis during glutamine deprivation. It does not establish that glutamate failed to rescue cell growth or mitochondrial respiration, or that mitochondrial GLS-catalyzed cleavage is essential for glutaminolysis. (LLM, conf=0.82)

  cites [43] Zhang, J. et al. Asparagine plays a critical role in regulating cellular adaptation to glutamine depletion. Mol. Cell 56, 205–218 (2014). sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction identifies glutamate as a product of GLS, and the section on rescuing glutamine-deprived endothelial cells reports impaired proliferation and incomplete rescue by several supplements. But the paper does not report that glutamate supplementation fails to rescue growth or mitochondrial respiration during glutamine deprivation. In fact, the section on endothelial-cell sprouting reports that exogenous glutamate reversed the anti-proliferative effect of GLS1 inhibition—a different condition that does not establish the claimed necessity of GLS-catalyzed cleavage. (LLM, conf=0.88)

  cites [44] Huang, H. et al. Role of glutamine and interlinked asparagine metabolism in vessel formation. Embo J. 36, 2334–2352 (2017). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section (‘Asparagine facilitates the expression of GLUL under glutamine deprivation’; page unavailable) reports that replacing glutamine with glutamate did not rescue proliferation of glutamine-depleted cells. Our copy does not report whether glutamate supplementation rescues mitochondrial respiration. The statement about essential mitochondrial GLS-catalyzed cleavage follows the citations as the citing authors’ inference, rather than a finding this citation directly supports. (LLM, conf=0.87)

  cites [45] Pavlova, N. N. et al. As extracellular glutamine levels decline, asparagine becomes an essential amino acid. Cell Metab. 27, 428 (2018). sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• ?Could not verify

  The section labeled Abstract says glutamate is converted to α-ketoglutarate in mitochondria, but does not address the claimed export to the cytosol. Searches for SLC25A11, fatty acid biosynthesis, and NADH generation found no passage supporting those claims; the paper discusses SLC1A5_var-mediated glutamine import and NADPH instead. (LLM, conf=0.75)

  cites [21] Stine, Z. E. & Dang, C. V. Glutamine skipping the Q into mitochondria. Trends Mol. Med. 26, 6–7 (2020). sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction (page unavailable) says AKG-derived citrate can supply acetyl-CoA for fatty acid biosynthesis, and the Results section on AKG dehydrogenase and NNT (page unavailable) says AKG oxidation generates NADH. However, the paper locates that NADH-generating activity in mitochondria; it does not establish that exported cytosolic AKG generates NADH. The SLC25A11 export clause is attached to citation 21, not this source’s citation 22. (LLM, conf=0.84)

  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). sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Supported

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

  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

In the paper

“Moreover, CB-839, the first glutaminase inhibitor, has entered several clinical trials14,15.”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“Thus, glutamine deprivation suppresses cancer growth and even induces cell death in several cancers6,7.”

What the sources say

• Not checked yetcites [6] Qing, G. et al. ATF4 regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation. Cancer Cell 22, 631–644 (2012). source
• Not checked yetcites [7] Chen, L. & Cui, H. Targeting glutamine induces apoptosis: a cancer therapy approach. Int. J. Mol. Sci. 16, 22830–22855 (2015). source

In the paper

“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.”

What the sources say

• Not checked yetcites [23] Yang, L. F., Venneti, S. & Nagrath, D. Glutaminolysis: a hallmark of cancer metabolism. Annu. Rev. Biomed. Eng. 19, 163–194 (2017). source

In the paper

“Cytosolic glutamine supports nucleotide biosynthesis, which is essential for rapidly proliferating cells30.”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“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.”

What the sources say

• Not checked yetcites [48] Coloff, J. L. et al. Differential glutamate metabolism in proliferating and quiescent mammary epithelial cells. Cell Metab. 23, 867–880 (2016). source
• Not checked yetcites [6] Qing, G. et al. ATF4 regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation. Cancer Cell 22, 631–644 (2012). source

In the paper

“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.”

What the sources say

• Not checked yetcites [31] Moffatt, B. A. & Ashihara, H. Purine and pyrimidine nucleotide synthesis and metabolism. Arabidopsis Book 1, e0018 (2002). source

In the paper

“Mitochondrial α-KG can then participate in the TCA cycle, supporting the oxidative phosphorylation (OXPHOS) pathway or the reductive carboxylation pathway23.”

What the sources say

• Not checked yetcites [23] Yang, L. F., Venneti, S. & Nagrath, D. Glutaminolysis: a hallmark of cancer metabolism. Annu. Rev. Biomed. Eng. 19, 163–194 (2017). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [31] Moffatt, B. A. & Ashihara, H. Purine and pyrimidine nucleotide synthesis and metabolism. Arabidopsis Book 1, e0018 (2002). source

In the paper

“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.”

What the sources say

• Not checked yetcites [45] Pavlova, N. N. et al. As extracellular glutamine levels decline, asparagine becomes an essential amino acid. Cell Metab. 27, 428 (2018). source

In the paper

“In cells with NRF2 activation, most glutamate is secreted, and cystine is imported by the SLC7A11 (xCT) antiporter mechanism47 (Fig. 3).”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [18] Wang, J. B. et al. Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell 18, 397–397 (2010). source
• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [43] Zhang, J. et al. Asparagine plays a critical role in regulating cellular adaptation to glutamine depletion. Mol. Cell 56, 205–218 (2014). source

In the paper

“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.”

What the sources say

• Not checked yetcites [38] Santana-Codina, N. et al. Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis. Nat. Commun. 9, 4945 (2018). source

In the paper

“PPAT transfers glutamine-derived nitrogen to 5-phosphoribosyl pyrophosphate (PRPP), and this step is considered the initial step in purine biosynthesis37.”

What the sources say

• Not checked yetcites [37] Lane, A. N. & Fan, T. W. Regulation of mammalian nucleotide metabolism and biosynthesis. Nucleic Acids Res. 43, 2466–2485 (2015). source

In the paper

“In addition, IDH1-dependent reductive glutamine metabolism produces NADPH, which decreases mitochondrial ROS during anchorage-independent growth64.”

What the sources say

• Not checked yetcites [64] Jiang, L. et al. Reductive carboxylation supports redox homeostasis during anchorage-independent growth. Nature 532, 255–258 (2016). source

In the paper

“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.”

What the sources say

• Not checked yetcites [72] Perez-Escuredo, J. et al. Lactate promotes glutamine uptake and metabolism in oxidative cancer cells. Cell Cycle 15, 72–83 (2016). source

In the paper

“Consistent with this observation, glutamine starvation has been associated with impaired uptake of cystine through xCT and decreased intracellular glutathione levels62.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“Recent studies suggest that cancer cells are under increased oxidative stress caused by oncogenic transformation, leading to metabolic alterations that result in ROS production56.”

What the sources say

• Not checked yetcites [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

In the paper

“Given that HIF-2α is an important transcription factor in cancer progression and leads to poor prognosis69,70”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [70] Li, Z. et al. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell 15, 501–513 (2009). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“This study suggested that l-asparaginase treatment alone can reduce the incidence of breast cancer metastasis to the lung without affecting primary tumor growth.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [81] Chen, W. et al. Targeting renal cell carcinoma with a HIF-2 antagonist. Nature 539, 112–117 (2016). source
• Not checked yetcites [82] Cho, H. et al. On-target efficacy of a HIF-2alpha antagonist in preclinical kidney cancer models. Nature 539, 107–111 (2016). source

In the paper

“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.”

What the sources say

• Not checked yetcites [67] Denko, N. C. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat. Rev. Cancer 8, 705–713 (2008). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [110] Petrus, P. et al. Glutamine links obesity to inflammation in human white adipose tissue. Cell Metab. 31, 375 (2020). source

In the paper

“Consistent with these findings, while NRF2 induces chemoresistance in KRAS-driven cancers, suppressing glutamine metabolism leads to weakened chemoresistance in these cancer cells85.”

What the sources say

• Not checked yetcites [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

In the paper

“In cancer cells, mutations in succinate dehydrogenase subunit B (SDHB) cause susceptibility to familial pheochromocytoma99 and familial paraganglioma100 as well as gastrointestinal stromal tumors101.”

What the sources say

• Not checked yetcites [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 yetcites [100] Letouze, E. et al. SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell 23, 739–752 (2013). source
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [105] TeSlaa, T. et al. alpha-Ketoglutarate accelerates the initial differentiation of primed human pluripotent stem cells. Cell Metab. 24, 485–493 (2016). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [125] Bardella, C., Pollard, P. J. & Tomlinson, I. SDH mutations in cancer. Biochim Biophys. Acta 1807, 1432–1443 (2011). source
• Not checked yetcites [126] Müller, S. N. U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat. Genet. 26, 268–270 (2000). source

In the paper

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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“Indeed, glutamine-derived R-2-HG accumulates and prevents the differentiation of myeloblasts, resulting in uncontrolled growth of blood cells122.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [100] Letouze, E. et al. SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell 23, 739–752 (2013). source

In the paper

“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.”

What the sources say

• Not checked yetcites [102] Killian, J. K. et al. Succinate dehydrogenase mutation underlies global epigenomic divergence in gastrointestinal stromal tumor. Cancer Discov. 3, 648–657 (2013). source

In the paper

“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).”

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“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”

What the sources say

• Not checked yetcites [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 yetcites [118] Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012). source

In the paper

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

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [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).

In the paper

“Upon glutamine starvation, p53 activity is induced and can help cancer cells adapt to nutrient starvation through diverse mechanisms148.”

What the sources say

• Not checked yetcites [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

In the paper

“In addition, fumarate inhibits TET enzymes, which stimulate EMT, leading to cancer metastasis131,132.”

What the sources say

• Not checked yetcites [131] Sciacovelli, M. et al. Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Nature 537, 544–547 (2016). source
• Not checked yetcites [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

In the paper

“In addition, mTORC1 activation via glutaminolysis suppresses autophagy and the DNA damage response164,165.”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“Specifically, autophagy suppresses anoikis induced by the detachment of cancer cells from the extracellular matrix (ECM) and hence promotes metastasis169.”

What the sources say

• Not checked yetcites [169] Debnath, J. Detachment-induced autophagy during anoikis and lumen formation in epithelial acini. Autophagy 4, 351–353 (2008). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [158] Eng, C. H. & Abraham, R. T. Glutaminolysis yields a metabolic by-product that stimulates autophagy. Autophagy 6, 968–970 (2010). source
• Not checked yetcites [159] Rabinowitz, J. D. & White, E. Autophagy and metabolism. Science 330, 1344–1348 (2010). source

In the paper

“Accordingly, high mTORC1 activity in cancer cells promotes aerobic glycolysis and drives glucose addiction162,163”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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.”

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [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 yetcites [174] Dang, C. V. Rethinking the Warburg effect with Myc micromanaging glutamine metabolism. Cancer Res. 70, 859–862 (2010). source
• Not checked yetcites [175] Hao, Y. et al. Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer. Nat. Commun. 7, 11971 (2016). source

In the paper

“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.”

What the sources say

• Not checked yetcites [166] Villar, V. H., Merhi, F., Djavaheri-Mergny, M. & Duran, R. V. Glutaminolysis and autophagy in cancer. Autophagy 11, 1198–1208 (2015). source

In the paper

“Collectively, cancer glutamine metabolism shows extraordinary flexibility and is intertwined with diverse metabolic pathways.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [129] Virpi Launonen, O. V. et al. Inherited susceptibility to uterine leiomyomas and renal cell cancer. PNAS 98, 3387–3392 (2001). source
• Not checked yetcites [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

In the paper

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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“Consistent with this observation, K-Ras sensitizes cells to glutamine deprivation, and K-Ras knockdown rescues cells from apoptosis induced by low glutamine levels187.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [200] Leone, R. D. et al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science 366, 1013 (2019). source

In the paper

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

In the paper

“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.”

What the sources say

• Not checked yetcites [160] Duran, R. V. & Hall, M. N. Glutaminolysis feeds mTORC1. Cell Cycle 11, 4107–4108 (2012). source

In the paper

“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.”

What the sources say

• Not checked yetcites [200] Leone, R. D. et al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science 366, 1013 (2019). source

In the paper

“Accordingly, loss of SIRT4 enhances glutamine-dependent proliferation and genomic instability, which simultaneously contribute to tumorigenesis151.”

What the sources say

• Not checked yetcites [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

In the paper

“In addition, SLC1A5 was shown to have clinical importance, and it is considered the most critical plasma membrane glutamine transporter in cancer cells201.”

What the sources say

• Not checked yetcites [201] Liu, Y. et al. The role of ASCT2 in cancer: a review. Eur. J. Pharm. 837, 81–87 (2018). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [207] Chiu, M. et al. GPNA inhibits the sodium-independent transport system L for neutral amino acids. Amino Acids 49, 1365–1372 (2017). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“Moreover, glutamine also acts as a precursor for the synthesis of various NEAAs, including asparagine and arginine, implicated in mTORC1 activation39.”

What the sources say

• Not checked yetcites [39] Choi, B. H. & Coloff, J. L. The diverse functions of non-essential amino acids in cancer. Cancers 11, 675 (2019). source