Glutamine reliance in cell metabolism

In the paper

“In the context of constitutive HIF-2α stabilization75 or a defective mitochondrial electron transport chain76, glutamine-derived α-KG is reductively carboxylated through the consumption of NADPH by IDH2 to generate citrate.”

What the sources say

• Partly supported

  In the passage on VHL-deficient renal carcinoma cells (section labeled Abstract; page unavailable), the paper reports increased reductive glutamine metabolism and shows that HIF-2α knockdown partially reverses the metabolic switch. But its IDH experiments implicate IDH1, not IDH2: IDH2 knockdown produced no significant change in reductive flux in the tested cell lines. The defective-electron-transport-chain context is attached to citation 76, not this source. (LLM, conf=0.88)

  cites [75] Metallo, C. M. et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481, 380–384 (2011). sourceExperimental — accuracy not yet measured
• Supported

  For the defective-electron-transport-chain portion cited to this paper, the main text reports that cells with ETC defects produce citrate by reductive carboxylation of glutamine-derived α-ketoglutarate (Fig. 1c). It identifies IDH2 as a contributing NADP+/NADPH-dependent enzyme (Fig. 2a,b), though IDH1 also contributes. The HIF-2α portion is attached to a different citation and is not judged here. (LLM, conf=0.92)

  cites [76] Mullen, A. R. et al. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 481, 385–388 (2011). source

In the paper

“Glutamine is considered the rate-limiting factor in glutathione synthesis58,59.”

What the sources say

• Not checked yetcites [58] Welbourne, T. C. Ammonia production and glutamine incorporation into glutathione in the functioning rat kidney. Can. J. Biochem. 57, 233–237 (1979). source
• Partly supported

  The Discussion reports that removing glutamine abolished glutathione synthesis and excretion in the studied lung cancer cells. That supports glutamine dependence in those cells, but the paper does not establish glutamine as the rate-limiting factor in glutathione synthesis generally. (LLM, conf=0.86)

  cites [59] Sappington, D. R. et al. Glutamine drives glutathione synthesis and contributes to radiation sensitivity of A549 and H460 lung cancer cell lines. Biochim. Biophys. Acta 1860, 836–843 (2016). sourceExperimental — accuracy not yet measured

In the paper

“Nevertheless, the specific metabolic importance of glutamine in tumorigenesis and tumor growth has also been reported194–196”

What the sources say

• Partly supported

  The Discussion (page unavailable) reports that blocking glutamine metabolism inhibited tumor-cell growth and reduced tumor xenograft growth in vivo. The paper also describes glutamine metabolism as important for cancer-cell survival and proliferation, but these findings do not directly establish a role in tumorigenesis. (LLM, conf=0.82)

  cites [194] Le, A. et al. Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab. 15, 110–121 (2012). sourceExperimental — accuracy not yet measured
• Supported

  The Introduction describes glutamine as a source of carbon and nitrogen for proliferating cancer cells and states that glutamine metabolism has a central role in cancer cell growth. It also reports that reducing glutaminase activity blunted tumor progression in a mouse model, supporting the claim about tumorigenesis and growth. (LLM, conf=0.91)

  cites [195] Xiang, Y. et al. Targeted inhibition of tumor-specific glutaminase diminishes cell-autonomous tumorigenesis. J. Clin. Invest. 125, 2293–2306 (2015). source
• Supported

  The Discussion reports that MYC-induced renal carcinoma cells were dependent on glutamine metabolism and that inhibiting glutaminase halted tumor growth in vitro and in vivo. The results section also links initiation of RCC in the mouse model to activation of glutaminolysis. These findings support the cited statement as an example of glutamine’s metabolic importance in tumorigenesis and growth. (LLM, conf=0.92)

  cites [196] Shroff, E. H. et al. MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism. Proc. Natl Acad. Sci. USA 112, 6539–6544 (2015). source

In the paper

“MYC-driven cancer cells exhibit enhanced glutamine utilization accompanied by increased expression of key glutaminolysis enzymes, including GLS1/GLS2 and GLUD1178–180.”

What the sources say

• Partly supported

  The main text reports that Myc increases glutaminase expression and glutamine catabolism, supporting the enhanced-utilization and GLS1 parts of the claim. But it says only GLS1 was predominantly expressed in the studied cells (passage 6), while glutamate dehydrogenase mRNA appeared unaltered (passage 2). It does not support increased GLS2 or GLUD1 expression. (LLM, conf=0.91)

  cites [178] Gao, P. et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458, 762–765 (2009). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section, “MYC and MET Differently Affect Glutamine Metabolism in the Liver” (page unavailable), reports increased glutamine transport and catabolism in MYC-induced liver tumors, with GLS1 replacing GLS2. The Results section on tissue context reports increased GLS1 in MYC-induced lung tumors but no change in GLS2. The claim is therefore supported for glutamine utilization and GLS1, not for increased GLS2; no passage found supports increased GLUD1 expression. (LLM, conf=0.91)

  cites [179] Yuneva, M. O. et al. The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type. Cell Metab. 15, 157–170 (2012). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section reports that N-Myc promotes glutamine metabolism through GLS2 in MYCN-amplified neuroblastoma cells. It also reports that GLS1 expression was reduced, not increased, in MYCN-amplified tumors; the Introduction describes c-Myc-associated GLS1 expression in other cancer cells. The passages do not support the attributed increase in GLUD1. (LLM, conf=0.90)

  cites [180] Xiao, D. et al. Myc promotes glutaminolysis in human neuroblastoma through direct activation of glutaminase 2. Oncotarget 6, 40655–40666 (2015). sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“specific genetic interference with glutaminase (GLS) inhibits tumor cell growth13.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

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

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“glutamine has been confirmed to be a major nutrient source for oxidative metabolism in some cancer cell lines10–12”

What the sources say

• Not checked yetcites [10] Eagle, H. Nutrition needs of mammalian cells in tissue culture. Science 122, 501–514 (1955). source
• Not checked yetcites [11] Kovacevic, Z. & Morris, H. P. The role of glutamine in the oxidative metabolism of malignant cells. Cancer Res. 32, 326–333 (1972).
• Not checked yetcites [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

In the paper

“Asparagine can be synthesized de novo from glutamine via asparagine synthetase (ASNS).”

In the paper

“Glutamate is also utilized to synthesize the antioxidant glutathione4.”

What the sources say

• Not checked yetcites [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

In the paper

“Notably, increased expression of the transcription factor MYC, which is strongly associated with glutamine metabolism, induces the expression of several key enzymes in nucleotide biosynthesis, including phosphoribosyl pyrophosphate amidotransferase (PPAT)36.”

What the sources say

• Not checked yetcites [36] Liu, Y. C. et al. Global regulation of nucleotide biosynthetic genes by c-Myc. PLoS ONE 3, e2722 (2008). source

In the paper

“In addition, NADPH generation via glutamine metabolism in cancer cells supports redox homeostasis by maintaining the cytosolic NADPH pool used to restore oxidized glutathione29 (Fig. 1).”

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

In the paper

“Notably, among NEAAs, the generation of glutamate and asparagine is directly dependent on glutamine (Fig. 3).”

In the paper

“This inability is probably due to the function of glutamine metabolism, which provides both carbon and nitrogen for cellular biogenesis.”

In the paper

“Thus, exogenous aspartate can restore cell cycle arrest caused by glutamine deprivation33.”

What the sources say

• Not checked yetcites [33] 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). source

In the paper

“Citrate, generated by reductive carboxylation of α-KG, is especially crucial for lipid synthesis under low-oxygen conditions24,25.”

What the sources say

• Not checked yetcites [24] Metallo, C. M. et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481, 380–U166 (2012). source
• Not checked yetcites [25] Sun, R. C. & Denko, N. C. Hypoxic regulation of glutamine metabolism through HIF1 and SIAH2 supports lipid synthesis that is necessary for tumor growth. Cell Metab. 19, 285–292 (2014). source

In the paper

“α-KG is considered an important cofactor for enzymes participating in epigenetic modification26.”

What the sources say

• Not checked yetcites [26] Lu, V. & Teitell, M. A. Alpha-ketoglutarate: a “magic” metabolite in early germ cell development. Embo J. 38, e100615 (2019). source

In the paper

“In addition, nitrogen derived from glutamine is required for the biosynthesis of molecules such as nucleotides, glucosamine, and NEAAs39.”

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

In the paper

“Additionally, glutamine-derived aspartate plays a crucial role in hypoxic environments or environments with electron transport chain (ETC) impairment28.”

What the sources say

• Not checked yetcites [28] Sullivan, L. B. et al. Supporting aspartate biosynthesis is an essential function of respiration in proliferating. Cell 162, 552–563 (2015). source

In the paper

“Glutamate, however, is a negatively charged amino acid, and most cancer cells export—instead of import—glutamate46.”

What the sources say

• Not checked yetcites [46] LeBoeuf, S. E. et al. Activation of oxidative stress response in cancer generates a druggable dependency on exogenous non-essential amino acids. Cell Metab. 31, 339 (2020). source

In the paper

“Although glutamine has been considered an NEAA that is synthesized endogenously, most cancer cells cannot proliferate or survive in a medium that does not contain glutamine5.”

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

“Interestingly, high intracellular asparagine levels have recently been identified to be essential for breast cancer metastasis51.”

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

“Interestingly, the first step in de novo pyrimidine biosynthesis mediated by CPSs occurs mainly in mitochondria via CPS1 in K-Ras/LKB1-mutant lung cancer cells32 (Fig. 2).”

What the sources say

• Not checked yetcites [32] Kim, J. et al. CPS1 maintains pyrimidine pools and DNA synthesis in KRAS/LKB1-mutant lung cancer cells. Nature 546, 168–172 (2017). source

In the paper

“Moreover, glutamine-induced activation of mTORC1 results in the phosphorylation of the enzyme complex called carbamoyl phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), which catalyzes the condensation reaction converting glutamine-derived nitrogen into the pyrimidine precursor orotate34,35.”

What the sources say

• Not checked yetcites [34] Ben-Sahra, I., Howell, J. J., Asara, J. M. & Manning, B. D. Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. Science 339, 1323–1328 (2013). source
• Not checked yetcites [35] Robitaille, A. M. et al. Quantitative phosphoproteomics reveal mTORC1 activates de novo pyrimidine synthesis. Science 339, 1320–1323 (2013). source

In the paper

“Glutamate consumption by aminotransferases to generate NEAAs has also been indicated to be required for tumor growth in diverse cancer types29,40–42.”

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 [40] Thornburg, J. M. et al. Targeting aspartate aminotransferase in breast cancer. Breast Cancer Res. 10, 1–12 (2008). source
• Not checked yetcites [41] Korangath, P. et al. Targeting glutamine metabolism in breast cancer with aminooxyacetate. Clin. Cancer Res. 21, 3263–3273 (2015). source
• Not checked yetcites [42] Liu, B. Y. et al. Overexpression of phosphoserine aminotransferase 1 (PSAT1) predicts poor prognosis and associates with tumor progression in human esophageal squamous cell carcinoma. Cell. Physiol. Biochem. 39, 395–406 (2016). source

In the paper

“Glutamine is transported into cells through plasma membrane glutamine transporters such as SLC1A5, SLC38A1, and SLC38A217”

What the sources say

• Not checked yetcites [17] Scalise, M., Pochini, L., Galluccio, M., Console, L. & Indiveri, C. Glutamine transport and mitochondrial metabolism in cancer cell growth. Front. Oncol. 7, 306 (2017). source

In the paper

“These studies suggest that most glutamine-dependent protein translation activities can still proceed under asparagine supplementation in a glutamine-deprived environment, although the exact mechanism is still unknown.”

In the paper

“Glutamate plays a central role in NEAA metabolism because it is crucial for the biosynthesis of alanine, aspartate, proline, and serine, which are in turn used for the biosynthesis of asparagine, arginine, cysteine, and glycine (Fig. 3).”

In the paper

“the mitochondrial glutamine transporter, encoded by a transcript variant of the SLC1A5 gene, which encodes a well-known plasma membrane glutamine transporter, was only recently discovered16.”

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

“Interestingly, asparagine was reported to be able to rescue cancer cells from glutamine deprivation-induced apoptosis43.”

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

“Mitochondrial glutamate generated via these catabolic pathways can be exported from mitochondria to the cytosol through the SLC25A18 and SLC25A22 transporters21”

What the sources say

• Not checked yetcites [21] Stine, Z. E. & Dang, C. V. Glutamine skipping the Q into mitochondria. Trends Mol. Med. 26, 6–7 (2020). source

In the paper

“Although cytosolic CPS2 can produce a cytosolic pool of carbamoyl phosphate, CPS1 is a major rate-limiting enzyme in pyrimidine biosynthesis using nitrogen released via mitochondrial glutaminolysis32.”

What the sources say

• Not checked yetcites [32] Kim, J. et al. CPS1 maintains pyrimidine pools and DNA synthesis in KRAS/LKB1-mutant lung cancer cells. Nature 546, 168–172 (2017). source

In the paper

“Aspartate, which is derived from the transamination of glutamine to form glutamate, participates in pyrimidine and purine biosynthesis28.”

What the sources say

• Not checked yetcites [28] Sullivan, L. B. et al. Supporting aspartate biosynthesis is an essential function of respiration in proliferating. Cell 162, 552–563 (2015). source

In the paper

“Cancer cells in tumors with IDH1 or IDH2 mutations show oncogenic activity by converting glutamine-derived α-KG to 2-hydroxyglutarate (2-HG), which competitively inhibits α-KG-dependent histone and DNA modification enzymes27.”

What the sources say

• Not checked yetcites [27] Chang, S., Yim, S. & Park, H. The cancer driver genes IDH1/2, JARID1C/KDM5C, and UTX/KDM6A: crosstalk between histone demethylation and hypoxic reprogramming in cancer metabolism. Exp. Mol. Med. 51, 66 (2019). source

In the paper

“For mitochondrial glutaminolysis, cytosolic glutamine must be transported through the inner mitochondrial membrane via the SLC1A5 variant, a mitochondrial glutamine transporter16.”

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

“Hypoxic conditions promote the uptake of glutamine by increasing the levels of glutamine transporters such as SLC1A5, the SLC1A5 variant, and SLC38A216,65”

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
• Not checked yetcites [65] Morotti, M. et al. Hypoxia-induced switch in SNAT2/SLC38A2 regulation generates endocrine resistance in breast cancer. Proc. Natl Acad. Sci. USA 116, 12452–12461 (2019). source

In the paper

“Impairing glutamine metabolism also induces sensitivity in gemcitabine-resistant pancreatic cancer cells16,84,85.”

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
• Not checked yetcites [84] Chen, R. et al. Disrupting glutamine metabolic pathways to sensitize gemcitabine-resistant pancreatic cancer. Sci. Rep. 7, 7950 (2017). source
• 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

“Glutamine acts as an alternative fuel for fatty acid synthesis, supplying citrate via mitochondrial reductive carboxylation, especially under hypoxic conditions74,75.”

What the sources say

• Not checked yetcites [74] Wise, D. R. et al. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of alpha-ketoglutarate to citrate to support cell growth and viability. Proc. Natl Acad. Sci. USA 108, 19611–19616 (2011). source
• Not checked yetcites [75] Metallo, C. M. et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481, 380–384 (2011). source

In the paper

“The metabolic pathway by which glutamine mitigates ROS is the glutathione synthesis pathway57 (Fig. 3).”

What the sources say

• Not checked yetcites [57] Amores-Sanchez, M. I. & Medina, M. A. Glutamine, as a precursor of glutathione, and oxidative stress. Mol. Genet. Metab. 67, 100–105 (1999). source

In the paper

“Next, mitochondrial citrate is transported across the inner mitochondrial membrane via a citrate carrier (CIC or SLC25A1) to support fatty acid synthesis for tumor progression in hypoxia73 (Fig. 4).”

What the sources say

• Not checked yetcites [73] Currie, E., Schulze, A., Zechner, R., Walther, T. C. & Farese, R. V. Jr. Cellular fatty acid metabolism and cancer. Cell Metab. 18, 153–161 (2013). source

In the paper

“and switch the fate of glutamine from the oxidative pathway into the reductive carboxylation pathway24.”

What the sources say

• Not checked yetcites [24] Metallo, C. M. et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481, 380–U166 (2012). source

In the paper

“Thus, HIF-2α-induced fatty acid synthesis using glutamine-derived citrate can be therapeutically targeted in several cancers, especially ccRCC.”

In the paper

“In pancreatic cancer cells, glutamine supports the production of NADPH via a noncanonical metabolic pathway29”

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

In the paper

“Fatty acid synthesis induced by HIF-2α is crucial for cell viability in ccRCC by sustaining endoplasmic reticulum (ER) homeostasis77.”

What the sources say

• Not checked yetcites [77] Qiu, B. et al. HIF2alpha-dependent lipid storage promotes endoplasmic reticulum homeostasis in clear-cell renal cell carcinoma. Cancer Discov. 5, 652–667 (2015). source

In the paper

“Fatty acid synthesis is an anabolic process that uses cytosolic citrate to produce acetyl-CoA73.”

What the sources say

• Not checked yetcites [73] Currie, E., Schulze, A., Zechner, R., Walther, T. C. & Farese, R. V. Jr. Cellular fatty acid metabolism and cancer. Cell Metab. 18, 153–161 (2013). source

In the paper

“Indeed, experiments using uniformly labeled 13C-glutamine showed that glutathione was enriched with five 13C atoms in glutathione, suggesting that glutamine is the major source of glutathione16,57,60.”

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
• Not checked yetcites [57] Amores-Sanchez, M. I. & Medina, M. A. Glutamine, as a precursor of glutathione, and oxidative stress. Mol. Genet. Metab. 67, 100–105 (1999). source
• Not checked yetcites [60] Tompkins, S. C. et al. Disrupting mitochondrial pyruvate uptake directs glutamine into the TCA cycle away from glutathione synthesis and impairs hepatocellular tumorigenesis. Cell Rep. 28, 2608–2619 (2019). source

In the paper

“For example, glutamine depletion has been shown to abolish hypoxia-induced chemoresistance in cholangiocarcinoma.”

In the paper

“This metabolic adaptation is critical because of the reduced entry of pyruvate into the TCA cycle by activated PDK1 and the increased lactate secretion in hypoxia66.”

What the sources say

• Not checked yetcites [66] Kim, J. W., Tchernyshyov, I., Semenza, G. L. & Dang, C. V. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 3, 177–185 (2006). source

In the paper

“In several cancers, glutamine metabolism is closely related to hypoxia-induced chemoresistance83.”

What the sources say

• Not checked yetcites [83] Wappler, J. et al. Glutamine deprivation counteracts hypoxia-induced chemoresistance. Neoplasia 22, 22–32 (2020). source

In the paper

“Although the clinical effect of l-asparaginase clearly indicates that asparagine is crucial for tumor survival and metastasis52, the importance of asparagine beyond protein synthesis and the mechanism by which asparagine supplementation enhances glutamine-associated metabolism are less well understood.”

What the sources say

• Not checked yetcites [52] Hill, J. M. et al. L-asparaginase therapy for leukemia and other malignant neoplasms. Remission in human leukemia. Jama 202, 882–888 (1967). source

In the paper

“and the mitochondrial glutamine transporter is strongly associated with glutaminolysis-induced NADPH generation16.”

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

“Furthermore, redox modulation augmented by increased glutathione synthesis from glutamine was reported to be the mechanism of resistance to gemcitabine 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

“Given the importance of glucose and glutamine metabolism in pancreatic cancer cells, it is not surprising that gemcitabine resistance is closely associated with metabolic status, including cellular glucose and glutamine levels.”

In the paper

“This bolstered chemoresistance in cancer cells is partially supported by glutathione synthesis via glutaminolysis86.”

What the sources say

• Not checked yetcites [86] Ju, H. Q. et al. Mechanisms of overcoming intrinsic resistance to gemcitabine in pancreatic ductal adenocarcinoma through the redox modulation. Mol. Cancer Ther. 14, 788–798 (2015). source

In the paper

“Furthermore, long-term exposure of cancer cells to acidic extracellular conditions induces metabolic reprogramming toward glutamine metabolism via HIF-2α activity71.”

What the sources say

• Not checked yetcites [71] Corbet, C. et al. The SIRT1/HIF2alpha axis drives reductive glutamine metabolism under chronic acidosis and alters tumor response to therapy. Cancer Res. 74, 5507–5519 (2014). source

In the paper

“Under these conditions, glutamine metabolism becomes essential for maintaining cellular redox homeostasis by harnessing enhanced ROS levels.”

In the paper

“these findings suggest that targeting HIF-2α might be an effective therapeutic strategy by inhibiting glutamine metabolism in these notorious cancers.”

In the paper

“Via this metabolic adaptation, cells can continually generate TCA metabolites, such as α-KG and citrate, which are converted to cytosolic acetyl-CoA for lipid biosynthesis (Fig. 4).”

In the paper

“As metabolites are the substrates used to generate chromatin modifications, including methylation and acetylation modifications of histones, a complicated interaction exists between metabolism and epigenetics.”

In the paper

“These reports suggest that α-KG generated via glutaminolysis is closely related to the cellular decisions that characterize stem cells.”

In the paper

“Acidic pH has also been reported to induce L-2-HG production via the promiscuous activity of LDHA and MDH enzymes.”

In the paper

“The metabolic state constitutes a fundamental component of chromatin modification and genome regulation97.”

What the sources say

• Not checked yetcites [97] Reid, M. A., Dai, Z. W. & Locasale, J. W. The impact of cellular metabolism on chromatin dynamics and epigenetics. Nat. Cell Biol. 19, 1298–1306 (2017). source

In the paper

“In addition to its role in cancer cells, α-KG supports the self-renewal of naive murine embryonic stem cells (mESCs) by promoting histone and DNA demethylation104.”

What the sources say

• Not checked yetcites [104] Carey, B. W., Finley, L. W., Cross, J. R., Allis, C. D. & Thompson, C. B. Intracellular alpha-ketoglutarate maintains the pluripotency of embryonic stem cells. Nature 518, 413–416 (2015). source

In the paper

“Interestingly, the generation of R-2-HG from glutamine has been proven to occur rapidly in patient-derived chondrosarcoma cell lines harboring endogenous IDH mutations”

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

“These studies suggest that targeting glutamine metabolism can be an effective cancer treatment strategy when combined with conventional anticancer chemotherapy.”

In the paper

“α-KG, also named 2-oxoglutarate, is a cofactor for 2-oxoglutarate-dependent dioxygenases (2-OGDDs), which catalyze hydroxylation reactions on diverse substrates.”

In the paper

“In addition, L-2-HG accumulation in an acidic pH environment has been reported to result in HIF-1α stabilization in normoxia91 (Fig. 4).”

What the sources say

• Not checked yetcites [91] Intlekofer, A. M. et al. L-2-hydroxyglutarate production arises from noncanonical enzyme function at acidic pH. Nat. Chem. Biol. 13, 494–500 (2017). source

In the paper

“In particular, glutamine-derived α-KG has been implicated in regulating cellular histone and DNA methylation levels98.”

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

“In skeletal stem cells (SSCs), GLS and glutamine metabolism are required for the regulation of osteoblast and adipocyte specification and physiological bone formation107.”

What the sources say

• Not checked yetcites [107] Yu, Y. et al. Glutamine metabolism regulates proliferation and lineage allocation in skeletal stem cells. Cell Metab. 29, 966–978 (2019). source

In the paper

“Among 2-OGDDs, Jumonji C domain-containing histone demethylases and ten-eleven translocation (TET) family DNA demethylases are major enzymes that induce epigenetic modifications using glutamine-derived α-KG.”

In the paper

“Under hypoxic conditions, L-2-hydroxyglutarate (L-2-HG) was proven to be generated by lactate dehydrogenase A (LDHA) and malate dehydrogenase (MDH)88,89.”

What the sources say

• Not checked yetcites [88] Intlekofer, A. M. et al. Hypoxia induces production of L-2-hydroxyglutarate. Cell Metab. 22, 304–311 (2015). source
• Not checked yetcites [89] Oldham, W. M., Clish, C. B., Yang, Y. & Loscalzo, J. Hypoxia-mediated increases in L-2-hydroxyglutarate coordinate the metabolic response to reductive stress. Cell Metab. 22, 291–303 (2015). source

In the paper

“As succinate accumulates via the inhibition of the 2-OGDD enzyme, epigenetic modification acts in the process of cell transformation into a hypermethylated phenotype100.”

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

“A high level of R-2-HG is sufficient to cause leukemia to arise from hematopoietic cells by maintaining their dedifferentiation and proliferation activities116.”

What the sources say

• Not checked yetcites [116] Losman, J. A. et al. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science 339, 1621–1625 (2013). source

In the paper

“Recently, glutamine metabolism has been shown to be linked to white adipose tissue (WAT) inflammation in obesity110.”

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

“The activities of 2-OGDDs are affected by the intracellular level of α-KG, succinate, fumarate, or 2-HG.”

In the paper

“Interestingly, patients with L-2-HGA are affected by tumors, including brain tumors93, bone tumors94, and nephroblastoma (Wilms tumor)95.”

What the sources say

• Not checked yetcites [93] Aghili, M., Zahedi, F. & Rafiee, E. Hydroxyglutaric aciduria and malignant brain tumor: a case report and literature review. J. NeuroOncol. 91, 233–236 (2009). source
• Not checked yetcites [94] Larnaout, A. et al. Osteoma of the calvaria in L-2-hydroxyglutaric aciduria. J. Inherit. Metab. Dis. 30, 980 (2007). source
• Not checked yetcites [95] Rogers, R. E. et al. Wilms tumor in a child with L-2-hydroxyglutaric aciduria. Pediatr. Dev. Pathol. 13, 408–411 (2010). source

In the paper

“Furthermore, increased L-2-HG levels caused by reduced expression of L2HGDH have been reported in renal cancer96.”

What the sources say

• Not checked yetcites [96] Shim, E. H. et al. L-2-Hydroxyglutarate: an epigenetic modifier and putative oncometabolite in renal cancer. Cancer Discov. 4, 1290–1298 (2014). source

In the paper

“In macrophage cells, α-KG produced via glutaminolysis promotes M2 activation via Jmjd3-dependent metabolic and epigenetic reprogramming108.”

What the sources say

• Not checked yetcites [108] Liu, P. S. et al. alpha-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Nat. Immunol. 18, 985 (2017). source

In the paper

“CB-839, a GLS inhibitor that blocks the conversion of glutamine into glutamate, reduced the production of R-2-HG in AML cell lines and patient tissues harboring IDH1/2 mutations123.”

What the sources say

• Not checked yetcites [123] Matre, P. et al. Inhibiting glutaminase in acute myeloid leukemia: metabolic dependency of selected AML subtypes. Oncotarget 7, 79722–79735 (2016). source

In the paper

“Thus, various tumors, including glioma, secondary glioblastoma, and acute myeloid leukemia (AML), harboring heterozygous point mutations in the active sites of IDH1/2 show dramatic increases in the R-2-HG levels111,113–115.”

What the sources say

• Not checked yetcites [111] Dang, L. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009). source
• Not checked yetcites [113] Ward, P. S. et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17, 225–234 (2010). source
• Not checked yetcites [114] Amary, M. F. et al. IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J. Pathol. 224, 334–343 (2011). source
• Not checked yetcites [115] Borger, D. R. et al. Circulating oncometabolite 2-hydroxyglutarate is a potential surrogate biomarker in patients with isocitrate dehydrogenase-mutant intrahepatic cholangiocarcinoma. Clin. Cancer Res. 20, 1884–1890 (2014). source

In the paper

“Collectively, glutamine-derived metabolites act as epigenetic modulators in a wide range of cell and tissue types, including various types of cancer cells, stem cells, immune cells, and even adipocytes.”

In the paper

“Furthermore, PSAT1 regulates changes in the level of glutamine-derived α-KG, which controls mESC pluripotency and differentiation106.”

What the sources say

• Not checked yetcites [106] Hwang, I. Y. et al. Psat1-dependent fluctuations in alpha-ketoglutarate affect the timing of ESC differentiation. Cell Metab. 24, 494–501 (2016). source

In the paper

“Homozygous L2HGDH mutations in germline transmission cause a disease named 2-hydroxyglutaric aciduria (L-2-HGA)92.”

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

“The cellular metabolic alteration of increased L-2-HG levels contributes to the regulation of histone and DNA methylation levels by inhibiting epigenetic modification enzymes that use α-ketoacid as a cofactor.”

In the paper

“Although additional studies are needed, ample experimental data support the recognition of R-2-HG, succinate, and fumarate as oncometabolites.”

What the sources say

• Not checked yetcites [111] Dang, L. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009). source
• Not checked yetcites [112] Martinez-Reyes, I. & Chandel, N. S. Mitochondrial TCA cycle metabolites control physiology and disease. Nat. Commun. 11, 102 (2020). source
• 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

“Further confirmation of fumarate as an oncometabolite was verified by experimental data showing that tumor cells lost their ability to invade and migrate when the function of fumarate hydratase was restored by an external expression vector131.”

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

In the paper

“Collectively, these observations indicate that anaplerotic glutamine metabolism is highly responsible for energy generation in cancer cells.”

In the paper

“Additionally, high levels of fumarate react with the cysteine group of mitochondrial aconitase-2 and iron-sulfur cluster binding protein-2, facilitating cellular metabolic adaptation to stresses138.”

What the sources say

• Not checked yetcites [138] Ternette, N. et al. Inhibition of mitochondrial aconitase by succination in fumarate hydratase deficiency. Cell Rep. 3, 689–700 (2013). source

In the paper

“Moreover, after the activation of K-Ras and Akt in transformed cells, 60% of the total FADH2 and NADH2 are synthesized from glutamine, while only 30% is derived from glucose140.”

What the sources say

• Not checked yetcites [140] Fan, J. et al. Glutamine-driven oxidative phosphorylation is a major ATP source in transformed mammalian cells in both normoxia and hypoxia. Mol. Syst. Biol. 9, 712 (2013). source

In the paper

“Recently, SLC1A3, as a crucial effector of p53, has been shown to support cell survival and growth in the absence of glutamine149.”

What the sources say

• Not checked yetcites [149] Tajan, M. et al. A role for p53 in the adaptation to glutamine starvation through the expression of SLC1A3. Cell Metab. 28, 721 (2018). source

In the paper

“Under these conditions, several studies have reported that glutamine supplementation can offer a therapeutic approach for these critical illnesses145–147.”

What the sources say

• Not checked yetcites [145] Ferreira, C. et al. Glutamine supplementation improves the efficacy of miltefosine treatment for visceral leishmaniasis. PLoS Negl. Trop. Dis. 14, e0008125 (2020). source
• Not checked yetcites [146] Gianotti, L., Alexander, J. W., Gennari, R., Pyles, T. & Babcock, G. F. Oral glutamine decreases bacterial translocation and improves survival in experimental gut-origin sepsis. J. Parenter. Enter. Nutr. 19, 69–74 (1995). source
• Not checked yetcites [147] Bakalar, B. et al. Parenterally administered dipeptide alanyl-glutamine prevents worsening of insulin sensitivity in multiple-trauma patients. Crit. Care Med. 34, 381–386 (2006). source

In the paper

“High concentrations of fumarate bind to glutathione, augmenting ROS signaling and accumulation, as observed in not only in vitro models but also in vivo models136,137.”

What the sources say

• Not checked yetcites [136] Sullivan, L. B. et al. The proto-oncometabolite fumarate binds glutathione to amplify ROS-dependent signaling. Mol. Cell 51, 236–248 (2013). source
• Not checked yetcites [137] Ooi, A. et al. An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer Cell 20, 511–523 (2011). source

In the paper

“In addition to the tumorigenic effects of succinate accumulation, SDH5 mutation is the key driver supporting the acquisition of epithelial–mesenchymal transition (EMT) characteristics.”

What the sources say

• Not checked yetcites [128] 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). source

In the paper

“Indeed, the process of adaptation to glutamine deprivation weakens the response to hypoxia, which normally strongly induces the expression of glycolytic enzymes83.”

What the sources say

• Not checked yetcites [83] Wappler, J. et al. Glutamine deprivation counteracts hypoxia-induced chemoresistance. Neoplasia 22, 22–32 (2020). source

In the paper

“Furthermore, autophagy has been shown to promote glycolysis in hepatocellular carcinoma (HCC) cells by upregulating monocarboxylate transporter 1 (MCT1), which plays an important role in the transport of lactic acid170.”

What the sources say

• Not checked yetcites [170] Fan, Q. et al. Autophagy promotes metastasis and glycolysis by upregulating MCT1 expression and Wnt/beta-catenin signaling pathway activation in hepatocellular carcinoma cells. J. Exp. Clin. Cancer Res. 37, 9 (2018). source

In the paper

“in addition, the expression of the SLC1A5 variant affected the levels of metabolites derived from glucose metabolism, including lactate and ribulose-5-phosphate, the intermediate metabolites in the PPP16.”

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

“Oncogenic Myc stimulates mitochondrial glutaminolysis via transcriptional regulation of genes necessary for cellular glutamine catabolism177.”

What the sources say

• Not checked yetcites [177] Wise, D. R. et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc. Natl Acad. Sci. USA 105, 18782–18787 (2008). source

In the paper

“The results of a clinical study further confirmed this observation by showing that patients with nonmetastatic lung cancer harbored loss-of-function mutations in SDH5128.”

What the sources say

• Not checked yetcites [128] 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). source

In the paper

“This PC-mediated alternative anaplerosis is considered important in specific types of cancers, including liver cancers and glioblastoma, for maintaining biosynthesis and redox homeostasis154–156.”

What the sources say

• Not checked yetcites [154] Jitrapakdee, S., Vidal-Puig, A. & Wallace, J. C. Anaplerotic roles of pyruvate carboxylase in mammalian tissues. Cell. Mol. Life Sci. 63, 843–854 (2006). source
• Not checked yetcites [155] Christen, S. et al. Breast cancer-derived lung metastases show increased pyruvate carboxylase-dependent anaplerosis. Cell Rep. 17, 837–848 (2016). source
• Not checked yetcites [156] Cappel, D. A. et al. Pyruvate-carboxylase-mediated anaplerosis promotes antioxidant capacity by sustaining TCA cycle and redox metabolism in liver. Cell Metab. 29, 1291–1305 (2019). source

In the paper

“Additionally, metabolic profiling has revealed that suppression of GLS1 induces a compensatory anaplerotic mechanism via pyruvate carboxylase (PC), which allows the release of a glutamine-independent supply of TCA intermediates by catalyzing the transformation of pyruvate to oxaloacetate153.”

What the sources say

• Not checked yetcites [153] Cheng, T. et al. Pyruvate carboxylase is required for glutamine-independent growth of tumor cells. Proc. Natl Acad. Sci. USA 108, 8674–8679 (2011). source

In the paper

“For instance, a recent study has shown that GLS1 inhibition induces an increase in mitochondrial glutamate-pyruvate transaminase 2 (GPT2) to assist in TCA cycle anaplerosis for sustaining cancer cell growth and survival152.”

What the sources say

• Not checked yetcites [152] Kim, M., Gwak, J., Hwang, S., Yang, S. & Jeong, S. M. Mitochondrial GPT2 plays a pivotal role in metabolic adaptation to the perturbation of mitochondrial glutamine metabolism. Oncogene 38, 4729–4738 (2019). source

In the paper

“Similar to succinate, fumarate contributes to the inactivation of PHD, stabilizing HIF proteins to promote cell survival133”

What the sources say

• Not checked yetcites [133] Isaacs, J. S. et al. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell 8, 143–153 (2005). source

In the paper

“Recently, glutamine was shown to be a major fuel for mitochondrial oxygen consumption in pancreatic cancer cells”

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

“During cellular stress, such as nutrient starvation and catabolic stress after trauma, surgery, infection, sepsis, or cancer cachexia, blood glutamine levels are severely decreased144.”

What the sources say

• Not checked yetcites [144] Andrews, F. J. & Griffiths, R. D. Glutamine: essential for immune nutrition in the critically ill. Br. J. Nutr. 87, S3–S8 (2002). source