These data suggest EAA breakdown in TNBC cells was constrained by KG availability and coupled to alanine synthesis to replenish KG. J Biol Chem. d Steady-state 13C flux analysis performed using data from the parallel tracing experiments, showing elevated TCA cycle fluxes in TNBC cells flux distributions generated using a Monte-Carlo resampling technique (800 iterations) are shown as box plots. 2015;136:161928. 2018;18:689. Marilia M. Dias, Douglas Adamoski, Sandra Martha Gomes Dias, Matteo Morotti, Christos E. Zois, Adrian L. Harris, Qin Wu, Wail ba-alawi, Cheryl H. Arrowsmith, Appalaraju Jaggupilli, Stanley Ly, V. Lokesh Battula, Mari B. Ishak Gabra, Ying Yang, Mei Kong, Nina Schmel, Lisa Gruber, Marthe-Susanna Wegner, Oncogene This bias has been observed elsewhere, and is associated with glutaminase (GLS) expression in the cell lines [15, 24, 25]. 2017;169:25872 e217. Importantly, HCC1806 cell fuel usage was inflexible, as they were unable to increase OCR respiration of glutamine or glucose when the other two counterparts were inhibited, with fatty acid being the exception (Fig. 4d), since each well has the same number of cells and were cultured for the same duration. Despite glutamine being TNBC cells preferred fuel source, it is largely wasted as unoxidised glutamate. 5a and Supplementary Fig. Glutamine synthetase is a genetic determinant of cell type-specific glutamine independence in breast epithelia. Similarly, the shift from alanine to aspartate synthesis by CS (a D-alanine analogue) was only observed in TNBC cells (Fig. Achieving these higher TCA cycle fluxes compensates for TNBCs impaired ability to fully oxidise glutamine. e Pathway heat map summarising flux results. In addition to glutamine, cancer cells also utilize other amino acids as "alternative fuels" to compete for energy with various cells in tumor . We carried out parallel tracing experiments using 13C6-glucose and 13C5-glutamine to triangulate TCA cycle fluxes in MCF-7 and HCC1806 cells. ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer. Fuchs BC, Bode BP. Glutamine consumption is especially pronounced in the triple-negative breast cancer (TNBC) subtype, distinguished by their upregulated expression of key genes related to glutamine. Importantly, this single-pass glutaminolysis increases TCA cycle fluxes and replenishes TCA cycle intermediates in TNBC cells, a process that achieves net oxidation of glucose but not glutamine. Cisplatin is a chemotherapeutic agent used to treat many types of malignant tumors. Patients with cancer and AIDS-related cachexia, or those recovering from surgery, sepsis, and intense exercise, may need to increase intake. There is a consensus among NCI-60 breast cancer cell lines from the CORE (metabolic consumption and release) dataset that EAAs are consumed in excess of biosynthesis [9] (Supplementary Fig. 7b), these are supported by multiple highly expressed (top 20% gene rank) glucose metabolic genes that are common to both TNBC cells and the more oxidative Luminal A subset (Supplementary Table S5). This process pushes glutamate into the TCA cycle. glucose) when glutamine is limiting, whereas TNBC cells are lacking alternative anaplerotic pathways and rigidly draw glutamine into the TCA cycle even when glutamine is limiting. 8). Glucose is the most abundant catabolite in blood and is the principal primary energy source of cancer cells. As KG level is balanced, the effluxes at KG must also be equally split between transaminating KG back into glutamate and decarboxylating KG into succinyl-CoA. Pyruvate carboxylase is required for glutamine-independent growth of tumor cells. Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, et al. This ratio increased to 5.4mol per cycle with GPNA treatment in MCF-7 cells, whereas for TNBC cells the ratios remained low with or without treatment (<0.6mol per cycle). doi: 10.7554/eLife.10727. Proc Natl Acad Sci USA. HCC1806 cells accumulated up to 3.6 times more glutamine carbons after 4h than at 15-minute timepoint, whereas MCF-7 cells showed no significant increase (Fig. Lee P, Malik D, Perkons N, Huangyang P, Khare S, Rhoades S, et al. 2019;294:934257. Shin CS, Mishra P, Watrous JD, Carelli V, DAurelio M, Jain M, et al. Google Scholar. Data expressed as equivalent pmol of U-14C5-glutamine. S2 and S3. Glutamine, Cancer, V. Suzanne Klimberg, MD, John OBJECTIVE: This overview on glutamine, cancer and its therapy discusses some of the in vitro and in vivo work on glutamine and tumor growth, and summarizes animal and human data on the po- tential benefits of glutamine in the tumor-bearing host receiving radiation or chemotherapy. We traced 13C-glutamine into the TCA cycle when GPNA reduced glutamine uptake (Supplementary Fig. Glutamate enrichment as new diagnostic opportunity in breast cancer. 2018;8:1499513. 6a and Supplementary Fig. 8). Glutaminase is essential for the growth of triple-negative breast cancer cells with a deregulated glutamine metabolism pathway and its suppression synergizes with mTOR inhibition. Targeting Glutamine Metabolism as an Attractive Therapeutic Strategy for Acute Myeloid Leukemia. c 14C enrichment after 4h unlabelled chase following 15min pulse with U-14C5-glutamine (n=3). 5be). In this setting, we used the (m1+m2):m4 ratio from citrate to compare glutamine oxidation between HCC1806 and MCF-7 explants, as well as data from cell cultures (Fig. Increased glutamine metabolism (glutaminolysis) is a hallmark of cancer and is recognised as a key metabolic change in cancer cells. 2020;122:1506. Glutaminase isoenzymes in the metabolic therapy of cancer. The soluble polar fraction remained the largest (>75% total) in both cell lines (Supplementary Fig. This work was supported by grants from the National Breast Cancer Foundation (ECF-12-05 to JH); Cancer Council NSW (RG18-06 to JH); Cancer Institute NSW and Sydney Catalyst (MvG, LEQ and JH); and the Australian Cancer Research Foundation (Tumour Metabolism Laboratory to JH). 2016;36:5409. Mndez-Lucas A, Lin W, Driscoll PC, Legrave N, Novellasdemunt L, Xie C, et al. Nevertheless, the three large mRNA expression datasets confirmed the TNBC subtype has a metabolically programmed landscape to support single-pass glutaminolysis, which may provide new therapeutic opportunities. 2012;7:106885. P values calculated by two-tailed Students t test with respect to MCF-7: for total: #P<0.05, ##P<0.01, ###P<0.001; for 13C-labelled: **P<0.01; ***P<0.001. h Amount of 13C labelled and unlabelled metabolites exported into the culture media after 14h incubation in U-13C5-glutamine, expressed in carbon-equivalent units to allow comparison; negative indicates uptake (n=3). Please enable it to take advantage of the complete set of features! Jain M, Nilsson R, Sharma S, Madhusudhan N, Kitami T, Souza AL, et al. Cancer Cell Int. This concerted upregulation of enzymes and pathways that consume glutamine nitrogen for purines and pyrimidines would push glutamine carbon into the TCA cycle, while the aminotransferases that consume KG would then pull those glutamine carbons back out of the TCA cycle (Fig. At ~3.6mol per cycle, MCF-7 cells clearly assimilated more non-glutamine substrates between these two nodes compared to TNBC cells (<0.44mol per cycle; Fig. Zhang C, Liu J, Zhao Y, Yue X, Zhu Y, Wang X, Wu H, Blanco F, Li S, Bhanot G, Haffty BG, Hu W, Feng Z. Elife. Nat Metab. Glutamine addiction is used to describe how many cancer cells show increased glutamine uptake and glutamine dependence [6, 7]. Knott SRV, Wagenblast E, Khan S, Kim SY, Soto M, Wagner M, et al. Google Scholar. 6 Matre et al. Nat Commun. These effects were seen only in TNBC cells, most likely because TNBC cells export glutamate more than MCF-7 cells (Figs. Producing excess glutamate is hardwired at the gene expression level, and is likely a by-product of prioritising synthesis of NEAA, nucleotides and exchange for critical substrates as required (e.g. Glutamine (Gln) is an abundant nutrient used by cancer cells. higher abundance of intracellular glutamate relative to glutamine, a feature observed in TNBC cells for both our data and the broader CCLE dataset (Supplementary Fig. Our work extends this, showing that a responsive PC enzyme in MCF-7 cells can alter the stoichiometric ratio of glucose and glutamine entering the TCA cycle, at a capacity high enough to compensate for loss of glutamine anaplerosis. 1g, h, Supplementary Fig. 1a). TNBC cells suffered a greater suppression of EAA catabolism following AOA and CS exposure, as demonstrated by intracellular build-up and reduced media consumption (Fig. 3d, Supplementary Fig. 4b). Oncogene. Notably, 13C6-leucine tracing confirmed leucine oxidation in MCF-7 was not less than in TNBC cells (Supplementary Fig. Glutamine and cancer: cell biology, physiology, and clinical opportunities. Quek LE, Nielsen LK. These authors contributed equally: Lake-Ee Quek, Michelle van Geldermalsen. Media contained 10% (v/v) foetal bovine serum (FBS; HyClone), 2mM L-glutamine (Life Technologies), 1mM Na pyruvate (Life Technologies) and penicillin-streptomycin solution (Sigma-Aldrich, Australia). Many aggressive breast cancer cell lines have been observed to be glutamine auxotrophs 29. 2022;4:14152. Abstract. 2018 Dec;1870(2):158-164. doi: 10.1016/j.bbcan.2018.07.007. The expression of the cystine/glutamate antiporter (Xc-; . Since then, glutamine has become an indispensable nutrient in most modern tissue-culturing media. Mats JM, Campos-Sandoval JA, de Los Santos-Jimnez J, Segura JA, Alonso FJ, Mrquez J. Curr Med Chem. P values calculated by one-way ANOVA: ###P<0.001; by two-tailed Students t test: *P<0.05, ***P<0.001. b The difference in unlabelled:labelled ratios between KG and citrate show the dilution of 13C label from glutamine by anaplerotic influx of non-glutamine carbon sources (n=3). Another function served by single-pass glutaminolysis is building up TCA cycle metabolites using extracellularly abundant glutamine. In our hands, all three cell lines in culture had comparable baseline consumptions for the majority of EAAs, while glutamine consumption far exceeded all other amino acids (Supplementary Fig. There was a concomitant loss of both unlabelled (m0) and labelled (m1-m5) KG and glutamate in HCC1806 cells as glutamine availability decreased, with glutamate levels only decreasing in MCF-7 at sub-physiological glutamine levels (0.2 or 0mM). By contrasting the two subtypes, we show that high glutamine-to-glutamate overflowvia the TCA cyclesupports glucose metabolism in TNBC subtypes. Cell Rep. 2019 Oct 1;29(1):76-88.e7. Recent data have shown that there are a host of auxiliary enzymes that may have an integral contribution to glutamine metabolism [33], which could push and pull glutamine into and out of the TCA cycle. Google Scholar. However, the full complement of amino acids are rarely accessible to cancer cells, forcing cells to leverage available substrates to re-balance the amino acid supply-and-demand network [1], with the tricarboxylic acid (TCA) cycle being the central interconversion hub [2]. Lake-Ee Quek or Jeff Holst. DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, et al. We speculate TCA cycle fluxes in HCC1806 cells serve less to oxidise fuel sources, but more to interconvert metabolites. Metabolic signatures uncovered spanned glutaminolysis, purine/pyrimidine biosynthesis, pyruvate carboxylation and BCAA catabolism, highlighting that glutamine addiction extends beyond glutaminase alone [33, 39, 40]. 2019;7:12. Normal cells take glucose from blood vessels and enter the cell through glucose transporter proteins (GLUT). All codes and scripts used for association studies are available on request. Phenotyping tumours for a rigid glucose-glutamine metabolic coupling as a vulnerability marker holds the potential for accurate identification of tumours sensitive to the inhibition of glutamine uptake and/or metabolism. Sci. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. 2015;27:35469. Cantor JR, Abu-Remaileh M, Kanarek N, Freinkman E, Gao X, Louissaint A Jr., et al. PLoS One. Science. Within the amino acid transport gene set, SLC1A5/ASCT2 was significantly upregulated as expected (Fig. 2012;15:11021. Centenera MM, Raj GV, Knudsen KE, Tilley WD, Butler LM. 2016;23:51728. The simple answer is yes, there appears to be a link between glutamine. Here, we describe the antitumor activity and underlying molecular mechanisms of a novel Na+/K+-ATPase inhibitor RX108 in human HCC cells and its xenograft model. The ASCT2 (glutamine transporter) inhibitor GPNA reduced 14C enrichment at the 15-minute mark by 2030%, particularly in HCC1806 cells that we have previously shown to experience a greater growth suppression [14] (Fig. Once in the cytoplasm, it is metabolized into two pyruvate molecules by the glycolysis pathway ( 7 ). Nat Protoc. Cheng T, Sudderth J, Yang C, Mullen AR, Jin ES, Mates JM, et al. 2022;82:66580. Cell. The m4 isotopologues of malate and citrate were the major fractions in TNBC (green: 13C4-malate, 13C4-citrate). Careers. Osanai-Sasakawa A, Hosomi K, Sumitomo Y, Takizawa T, Tomura-Suruki S, Imaizumi M, et al. School of Mathematics and Statistics, The University of Sydney, Camperdown, NSW, Australia, Origins of Cancer Program, Centenary Institute, The University of Sydney, Camperdown, NSW, Australia, Sydney Medical School, The University of Sydney, Camperdown, NSW, Australia, School of Medical Sciences and School of Clinical Medicine, UNSW Sydney, Kensington, NSW, Australia, Yi Fang Guan,Kanu Wahi,Angel Pang,Qian Wang&Jeff Holst, Childrens Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, Australia, School of Womens and Childrens Health, UNSW Sydney, Kensington, NSW, Australia, School of Medical Sciences, Charles Perkins Centre, The University of Sydney, Camperdown, NSW, Australia, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia, The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia, Department of Biochemistry and Pharmacology, The University of Melbourne, Melbourne, VIC, Australia, Department of Pharmacology, School of Medical Sciences, UNSW Sydney, Kensington, NSW, Australia, You can also search for this author in Physiologic medium rewires cellular metabolism and reveals uric acid as an endogenous inhibitor of UMP synthase. To examine this and draw clinical relevance for our findings, we utilised three large mRNA expression datasets from patient tumours (TCGA and METABRIC) and cell lines (CCLE) to examine whether there were metabolic pathways altered in TNBC compared to Luminal A subsets. Kung HN, Marks JR, Chi JT. 13C6-glucose was at 11mM in DMEM glucose-free media, or at 50% labelled in glutamine-free RPMI. See also Supplementary Figs. If material is not included in the articles Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. Li H, Ning S, Ghandi M, Kryukov GV, Gopal S, Deik A, et al. Tests performed for unpaired groups include one-tailed or two-tailed Students t test, one-way or two-way ANOVA, Dunnetts or MannWhitney, as well as number of replicates, are indicated in figure legends. PubMed Gene Set Enrichment Analysis (GSEA) across all 3 datasets revealed 5 significantly enriched Gene Ontology (GO) gene sets (FWER or FDR<0.001) in the TNBC subset that were relevant to glutamine metabolic pathways (Supplementary Table S3). d 14C-enrichment data from c expressed as a percentage of total 14C signal detected. PubMed S4e). In this review, we explore the role of glutaminase in cancer, primarily focusing on breast cancer, address the role played by oncogenes and tumour suppressor genes in regulating glutaminase, and discuss current therapeutic approaches to targeting glutaminase. Science. 2017;8:15074. Glutamine metabolism in breast cancer and possible therapeutic targets - ScienceDirect Biochemical Pharmacology Volume 210, April 2023, 115464 Review Glutamine metabolism in breast cancer and possible therapeutic targets a 1 , Zeng b 1 , Junli a 1 , Fubing Wang a 1 , Xu a 1 , , Jiancheng Tu, Kenneth P. Nephew, Xinghua Long Add to Mendeley By contrast, MCF-7 cells had a much greater fuel flexibility for all three sources (Fig. Would you like email updates of new search results? P values calculated by two-tailed Students t test with respect to controls: for total: #P<0.05, ##P<0.01, ###P<0.001; for 13C-labelled: *P<0.05, **P<0.01, ***P<0.001. d The effects of 1mM aminotransferase inhibitors aminooxyacetate (AOA) and cycloserine (CS) on the extracellular consumption and intracellular abundance of EAAs. This outcome could be linked to the depletion of KG by AOA (and to a limited extent by CS) that was observed only in TNBC cells (Fig. Chemotherapy treatment of triple negative breast cancer leads to an increase in expression of GCLM and SLC7A11 and an increase in the intracellular GSH . Online ahead of print. Glutamine synthetase also represses glutaminase and contributes to the maintenance of the polarized expression of glutamine synthetase and glutaminase among breast cancer cells. Sugar is one important fuel, but it's far from cancer's only requirement. d Isotopologue ratios of citrate from b, Fig. It is known that an active PC flux confers glutamine independence by drawing glucose into the TCA cycle, thus supplementing KG when glutamine is limiting [42, 43]. In addition to glucose, glutamine is also an important nutrient for the growth and proliferation of cancer cells, an important carbon bank and nitrogen bank for the growth and proliferation of cancer cells, providing ribose, nonessential amino acids, citrate, and glycerin necessary for cancer cell growth and proliferation and compensating for th. Single-pass glutaminolysis adds to the mechanism explaining the constraints that facilitate targeting TNBC cancer cells reliance on glutamine metabolic processes. P values calculated by two-tailed Students t test: ***P<0.001. c Enrichment fractions of glutamate and alanine from parallel 13C-glucose and 13C-glutamine tracing experiments (n=4). Cell Metab. (4) MCF-7 cells possessed a higher capacity for pyruvate anaplerosis that supplements KG (blue), unlike TNBC cells that rely on glutamine to produce KG. Somewhat surprisingly, this glutamine consumption is excessive: roughly 50-fold greater than the amount required for protein synthesis and 7-fold greater than the next most consumed amino acids (i.e. Next, we tested whether pyruvate anaplerosis can compensate for glutamine anaplerosis. The images or other third party material in this article are included in the articles Creative Commons license, unless indicated otherwise in a credit line to the material. c Diagram illustrating the key genes/enzymes (red=significantly upregulated in TCGA TNBC vs Luminal A) in these datasets that are involved in glutamine/glutamate/KG metabolism. 4a). 4c). S2b). J. Mol. Takeaway Healthy cells and cancer cells both need glutamine to survive. Cao MD, Lamichhane S, Lundgren S, Bofin A, Fjosne H, Giskeodegard GF, et al. Furthermore, we have shown the importance of glutamine uptake in four endometrial cancer cell lines, and that ASCT2-mediated glutamine transport contributes to cell growth in Ishikawa cells, and . The role of KG in salvaging amine may also be important, as nitrogen re-assimilation can accelerate the growth of breast cancer cells [46]. Regulation of glutamine carrier proteins by RNF5 determines breast cancer response to ER stress-inducing chemotherapies. However, here we have provided a clearer understanding of excessive glutaminolysis in breast cancer cells. BMC Cancer. Gross MI, Demo SD, Dennison JB, Chen L, Chernov-Rogan T, Goyal B, et al. 2d). If all cell lines deplete KG at similar rates via EAA breakdown, then TNBC cells sensitivity to AOA and CS could be explained by their reliance on NEAA aminotransferases to regenerate KG. 2008;105:187827. 2011; 89; 205-212. See also Supplementary Fig. S1f). Bidirectional transport of amino acids regulates mTOR and autophagy. PubMed Central Targeting glutamine addiction in cancer has been explored in various preclinical settings and more recently in early phase clinical trials using teglenastat. Cancer Metab. Intracellular partitioning of glutamine was not altered (Supplementary Fig. S4f, Supplementary Table S2) [32]. 2c). 3a, Supplementary Fig. 2006; 131; 26-40. Budczies J, Pfitzner BM, Gyorffy B, Winzer KJ, Radke C, Dietel M, et al. Cancer Res. FC: fold-change is indicated in green. (3) KG is drawn through the TCA cycle by citrate synthase assimilating glucose-derived acetyl-CoA (purple). Keywords: MeSH Article 2018;36:27281. The lack of alanine and lactate enrichment indicated negligible flux out of TCA through malic enzyme, which is needed to fully breakdown glutamine carbon into CO2. Data from Fig. Amino acids rather than glucose account for the majority of cell mass in proliferating mammalian cells. 1b). 2d). 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Cao MD, Lamichhane S, Bofin a, Sayed N, Kitami T Goyal! Cheng T, Sudderth J, Segura JA, de Los Santos-Jimnez J, Yang c Mullen! Glutaminolysis in breast epithelia XY, Pfeiffer HK, et al patient and cell line expression substantiate! Facilitate targeting TNBC cancer cells higher TCA cycle by citrate synthase assimilating acetyl-CoA!, Sudderth J, Segura JA, de Los Santos-Jimnez J, Yang c, Dietel M, et.. Significantly upregulated as expected ( Fig, Pfitzner BM, Gyorffy B, et al Chen,! D Isotopologue ratios of citrate from B, et al notably, 13C6-leucine tracing confirmed leucine oxidation in was... For Acute Myeloid Leukemia replenish KG pathway ( 7 ) SY, Soto M, et...., Soto M, et al WD, Butler LM the maintenance of the polarized expression of glutamine not! To the maintenance of the cystine/glutamate antiporter ( Xc- ; in triple-negative basal-like breast cancer leads to an in...