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Glutamate-oxaloacetate transaminase activity promotes palmitate lipotoxicity in rat hepatocytes by enhancing anaplerosis and citric acid cycle flux.
Egnatchik RA, Leamy AK, Sacco SA, Cheah YE, Shiota M, Young JD
(2019) J Biol Chem 294: 3081-3090
MeSH Terms: Animals, Aspartate Aminotransferases, Cell Death, Cell Line, Citric Acid Cycle, Extracellular Space, Glutamine, Hepatocytes, Ketoglutaric Acids, Male, Oxidative Stress, Oxygen, Palmitates, Rats, Rats, Sprague-Dawley
Show Abstract · Added March 28, 2019
Hepatocyte lipotoxicity is characterized by aberrant mitochondrial metabolism, which predisposes cells to oxidative stress and apoptosis. Previously, we reported that translocation of calcium from the endoplasmic reticulum to mitochondria of palmitate-treated hepatocytes activates anaplerotic flux from glutamine to α-ketoglutarate (αKG), which subsequently enters the citric acid cycle (CAC) for oxidation. We hypothesized that increased glutamine anaplerosis fuels elevations in CAC flux and oxidative stress following palmitate treatment. To test this hypothesis, primary rat hepatocytes or immortalized H4IIEC3 rat hepatoma cells were treated with lipotoxic levels of palmitate while modulating anaplerotic pathways leading to αKG. We found that culture media supplemented with glutamine, glutamate, or dimethyl-αKG increased palmitate lipotoxicity compared with media that lacked these anaplerotic substrates. Knockdown of glutamate-oxaloacetate transaminase activity significantly reduced the lipotoxic effects of palmitate, whereas knockdown of glutamate dehydrogenase (Glud1) had no effect on palmitate lipotoxicity. C flux analysis of H4IIEC3 cells co-treated with palmitate and the pan-transaminase inhibitor aminooxyacetic acid confirmed that reductions in lipotoxic markers were associated with decreases in anaplerosis, CAC flux, and oxygen consumption. Taken together, these results demonstrate that lipotoxic palmitate treatments enhance anaplerosis in cultured rat hepatocytes, causing a shift to aberrant transaminase metabolism that fuels CAC dysregulation and oxidative stress.
© 2019 Egnatchik et al.
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15 MeSH Terms
xCT (SLC7A11)-mediated metabolic reprogramming promotes non-small cell lung cancer progression.
Ji X, Qian J, Rahman SMJ, Siska PJ, Zou Y, Harris BK, Hoeksema MD, Trenary IA, Heidi C, Eisenberg R, Rathmell JC, Young JD, Massion PP
(2018) Oncogene 37: 5007-5019
MeSH Terms: 3T3 Cells, A549 Cells, Amino Acid Transport System y+, Animals, Carcinoma, Non-Small-Cell Lung, Cell Line, Cell Line, Tumor, Cell Proliferation, Cell Survival, Cystine, Cytoplasm, Disease Progression, Female, Glutamine, Humans, Lung Neoplasms, Male, Mice, Middle Aged
Show Abstract · Added March 28, 2019
Many tumors increase uptake and dependence on glucose, cystine or glutamine. These basic observations on cancer cell metabolism have opened multiple new diagnostic and therapeutic avenues in cancer research. Recent studies demonstrated that smoking could induce the expression of xCT (SLC7A11) in oral cancer cells, suggesting that overexpression of xCT may support lung tumor progression. We hypothesized that overexpression of xCT occurs in lung cancer cells to satisfy the metabolic requirements for growth and survival. Our results demonstrated that 1) xCT was highly expressed at the cytoplasmic membrane in non-small cell lung cancer (NSCLC), 2) the expression of xCT was correlated with advanced stage and predicted a worse 5-year survival, 3) targeting xCT transport activity in xCT overexpressing NSCLC cells with sulfasalazine decreased cell proliferation and invasion in vitro and in vivo and 4) increased dependence on glutamine was observed in xCT overexpressed normal airway epithelial cells. These results suggested that xCT regulate metabolic requirements during lung cancer progression and be a potential therapeutic target in NSCLC.
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Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models.
Schulte ML, Fu A, Zhao P, Li J, Geng L, Smith ST, Kondo J, Coffey RJ, Johnson MO, Rathmell JC, Sharick JT, Skala MC, Smith JA, Berlin J, Washington MK, Nickels ML, Manning HC
(2018) Nat Med 24: 194-202
MeSH Terms: Amino Acid Transport System ASC, Animals, Cell Line, Tumor, Cell Proliferation, Computer Simulation, Disease Models, Animal, Glutamine, HCT116 Cells, Humans, Mice, Minor Histocompatibility Antigens, Neoplasms, Oxidative Stress, Signal Transduction, Small Molecule Libraries
Show Abstract · Added March 14, 2018
The unique metabolic demands of cancer cells underscore potentially fruitful opportunities for drug discovery in the era of precision medicine. However, therapeutic targeting of cancer metabolism has led to surprisingly few new drugs to date. The neutral amino acid glutamine serves as a key intermediate in numerous metabolic processes leveraged by cancer cells, including biosynthesis, cell signaling, and oxidative protection. Herein we report the preclinical development of V-9302, a competitive small molecule antagonist of transmembrane glutamine flux that selectively and potently targets the amino acid transporter ASCT2. Pharmacological blockade of ASCT2 with V-9302 resulted in attenuated cancer cell growth and proliferation, increased cell death, and increased oxidative stress, which collectively contributed to antitumor responses in vitro and in vivo. This is the first study, to our knowledge, to demonstrate the utility of a pharmacological inhibitor of glutamine transport in oncology, representing a new class of targeted therapy and laying a framework for paradigm-shifting therapies targeting cancer cell metabolism.
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15 MeSH Terms
The receptor tyrosine kinase EphA2 promotes glutamine metabolism in tumors by activating the transcriptional coactivators YAP and TAZ.
Edwards DN, Ngwa VM, Wang S, Shiuan E, Brantley-Sieders DM, Kim LC, Reynolds AB, Chen J
(2017) Sci Signal 10:
MeSH Terms: Adaptor Proteins, Signal Transducing, Amino Acid Transport System ASC, Animals, Biomarkers, Tumor, Breast Neoplasms, DNA-Binding Proteins, Disease Models, Animal, Ephrin-A2, Female, Glutaminase, Glutamine, Humans, Intracellular Signaling Peptides and Proteins, Mice, Mice, Knockout, Minor Histocompatibility Antigens, Muscle Proteins, Phosphoproteins, Transcription Factors, Tumor Cells, Cultured
Show Abstract · Added April 2, 2019
Malignant tumors reprogram cellular metabolism to support cancer cell proliferation and survival. Although most cancers depend on a high rate of aerobic glycolysis, many cancer cells also display addiction to glutamine. Glutamine transporters and glutaminase activity are critical for glutamine metabolism in tumor cells. We found that the receptor tyrosine kinase EphA2 activated the TEAD family transcriptional coactivators YAP and TAZ (YAP/TAZ), likely in a ligand-independent manner, to promote glutamine metabolism in cells and mouse models of HER2-positive breast cancer. Overexpression of EphA2 induced the nuclear accumulation of YAP and TAZ and increased the expression of YAP/TAZ target genes. Inhibition of the GTPase Rho or the kinase ROCK abolished EphA2-dependent YAP/TAZ nuclear localization. Silencing or substantially reduced the amount of intracellular glutamate through decreased expression of and , respectively, genes that encode proteins that promote glutamine uptake and metabolism. The regulatory DNA elements of both and contain TEAD binding sites and were bound by TEAD4 in an EphA2-dependent manner. In patient breast cancer tissues, expression positively correlated with that of and , as well as that of and Although high expression of predicted enhanced metastatic potential and poor patient survival, it also rendered HER2-positive breast cancer cells more sensitive to glutaminase inhibition. The findings define a previously unknown mechanism of EphA2-mediated glutaminolysis through YAP/TAZ activation in HER2-positive breast cancer and identify potential therapeutic targets in patients.
Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Interrupted Glucagon Signaling Reveals Hepatic α Cell Axis and Role for L-Glutamine in α Cell Proliferation.
Dean ED, Li M, Prasad N, Wisniewski SN, Von Deylen A, Spaeth J, Maddison L, Botros A, Sedgeman LR, Bozadjieva N, Ilkayeva O, Coldren A, Poffenberger G, Shostak A, Semich MC, Aamodt KI, Phillips N, Yan H, Bernal-Mizrachi E, Corbin JD, Vickers KC, Levy SE, Dai C, Newgard C, Gu W, Stein R, Chen W, Powers AC
(2017) Cell Metab 25: 1362-1373.e5
MeSH Terms: Amino Acid Transport Systems, Neutral, Animals, Cell Proliferation, Glucagon, Glutamine, Liver, Mice, Mice, Knockout, Signal Transduction, Zebrafish, Zebrafish Proteins
Show Abstract · Added September 21, 2018
Decreasing glucagon action lowers the blood glucose and may be useful therapeutically for diabetes. However, interrupted glucagon signaling leads to α cell proliferation. To identify postulated hepatic-derived circulating factor(s) responsible for α cell proliferation, we used transcriptomics/proteomics/metabolomics in three models of interrupted glucagon signaling and found that proliferation of mouse, zebrafish, and human α cells was mTOR and FoxP transcription factor dependent. Changes in hepatic amino acid (AA) catabolism gene expression predicted the observed increase in circulating AAs. Mimicking these AA levels stimulated α cell proliferation in a newly developed in vitro assay with L-glutamine being a critical AA. α cell expression of the AA transporter Slc38a5 was markedly increased in mice with interrupted glucagon signaling and played a role in α cell proliferation. These results indicate a hepatic α islet cell axis where glucagon regulates serum AA availability and AAs, especially L-glutamine, regulate α cell proliferation and mass via mTOR-dependent nutrient sensing.
Copyright © 2017 Elsevier Inc. All rights reserved.
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Non-Invasive Glutamine PET Reflects Pharmacological Inhibition of BRAF In Vivo.
Schulte ML, Hight MR, Ayers GD, Liu Q, Shyr Y, Washington MK, Manning HC
(2017) Mol Imaging Biol 19: 421-428
MeSH Terms: Amino Acid Transport System ASC, Animals, Cell Line, Tumor, Colonic Neoplasms, Female, Glutamine, Humans, Liver Neoplasms, Mice, Nude, Minor Histocompatibility Antigens, Mutation, Positron-Emission Tomography, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Xenograft Model Antitumor Assays
Show Abstract · Added April 6, 2017
PURPOSE - This study aimed to study whether cancer cells possess distinguishing metabolic features compared with surrounding normal cells, such as increased glutamine uptake. Given this, quantitative measures of glutamine uptake may reflect critical processes in oncology. Approximately, 10 % of patients with colorectal cancer (CRC) express BRAF , which may be actionable with selective BRAF inhibitors or in combination with inhibitors of complementary signaling axes. Non-invasive and quantitative predictive measures of response to these targeted therapies remain poorly developed in this setting. The primary objective of this study was to explore 4-[F]fluoroglutamine (4-[F]F-GLN) positron emission tomography (PET) to predict response to BRAF-targeted therapy in preclinical models of colon cancer.
PROCEDURES - Tumor microarrays from patients with primary human colon cancers (n = 115) and CRC liver metastases (n = 111) were used to evaluate the prevalence of ASCT2, the primary glutamine transporter in oncology, by immunohistochemistry. Subsequently, 4-[F]F-GLN PET was evaluated in mouse models of human BRAF -expressing and BRAF wild-type CRC.
RESULTS - Approximately 70 % of primary colon cancers and 53 % of metastases exhibited positive ASCT2 immunoreactivity, suggesting that [F]4-F-GLN PET could be applicable to a majority of patients with colon cancer. ASCT2 expression was not associated selectively with the expression of mutant BRAF. Decreased 4-[F]F-GLN predicted pharmacological response to single-agent BRAF and combination BRAF and PI3K/mTOR inhibition in BRAF -mutant Colo-205 tumors. In contrast, a similar decrease was not observed in BRAF wild-type HCT-116 tumors, a setting where BRAF-targeted therapies are ineffective.
CONCLUSIONS - 4-[F]F-GLN PET selectively reflected pharmacodynamic response to BRAF inhibition when compared with 2-deoxy-2[F]fluoro-D-glucose PET, which was decreased non-specifically for all treated cohorts, regardless of downstream pathway inhibition. These findings illustrate the utility of non-invasive PET imaging measures of glutamine uptake to selectively predict response to BRAF-targeted therapy in colon cancer and may suggest further opportunities to inform colon cancer clinical trials using targeted therapies against MAPK activation.
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15 MeSH Terms
The Ephrin-A1/EPHA2 Signaling Axis Regulates Glutamine Metabolism in HER2-Positive Breast Cancer.
Youngblood VM, Kim LC, Edwards DN, Hwang Y, Santapuram PR, Stirdivant SM, Lu P, Ye F, Brantley-Sieders DM, Chen J
(2016) Cancer Res 76: 1825-36
MeSH Terms: Animals, Breast Neoplasms, Cell Proliferation, Ephrin-A1, Female, Glutamine, Humans, Mice, Receptor, EphA2, Signal Transduction
Show Abstract · Added February 7, 2019
Dysregulation of receptor tyrosine kinases (RTK) contributes to cellular transformation and cancer progression by disrupting key metabolic signaling pathways. The EPHA2 RTK is overexpressed in aggressive forms of breast cancer, including the HER2(+) subtype, and correlates with poor prognosis. However, the role of EPHA2 in tumor metabolism remains unexplored. In this study, we used in vivo and in vitro models of HER2-overexpressing breast cancer to investigate the mechanisms by which EPHA2 ligand-independent signaling promotes tumorigenesis in the absence of its prototypic ligand, ephrin-A1. We demonstrate that ephrin-A1 loss leads to upregulated glutamine metabolism and lipid accumulation that enhanced tumor growth. Global metabolic profiling of ephrin-A1-null, HER2-overexpressing mammary tumors revealed a significant increase in glutaminolysis, a critical metabolic pathway that generates intermediates for lipogenesis. Pharmacologic inhibition of glutaminase activity reduced tumor growth in both ephrin-A1-depleted and EPHA2-overexpressing tumor allografts in vivo Mechanistically, we show that the enhanced proliferation and glutaminolysis in the absence of ephrin-A1 were attributed to increased RhoA-dependent glutaminase activity. EPHA2 depletion or pharmacologic inhibition of Rho, glutaminase, or fatty acid synthase abrogated the increased lipid content and proliferative effects of ephrin-A1 knockdown. Together, these findings highlight a novel, unsuspected connection between the EPHA2/ephrin-A1 signaling axis and tumor metabolism, and suggest potential new therapeutic targets in cancer subtypes exhibiting glutamine dependency. Cancer Res; 76(7); 1825-36. ©2016 AACR.
©2016 American Association for Cancer Research.
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2-Amino-4-bis(aryloxybenzyl)aminobutanoic acids: A novel scaffold for inhibition of ASCT2-mediated glutamine transport.
Schulte ML, Khodadadi AB, Cuthbertson ML, Smith JA, Manning HC
(2016) Bioorg Med Chem Lett 26: 1044-1047
MeSH Terms: Amino Acid Transport System ASC, Animals, Binding Sites, Butyrates, Cell Line, Glutamine, HEK293 Cells, Humans, Minor Histocompatibility Antigens, Molecular Docking Simulation, Protein Structure, Tertiary, Rats, Structure-Activity Relationship
Show Abstract · Added February 11, 2016
Herein, we report the discovery of 2-amino-4-bis(aryloxybenzyl)aminobutanoic acids as novel inhibitors of ASCT2(SLC1A5)-mediated glutamine accumulation in mammalian cells. Focused library development led to two novel ASCT2 inhibitors that exhibit significantly improved potency compared with prior art in C6 (rat) and HEK293 (human) cells. The potency of leads reported here represents a 40-fold improvement over our most potent, previously reported inhibitor and represents, to our knowledge, the most potent pharmacological inhibitors of ASCT2-mediated glutamine accumulation in live cells. These and other compounds in this novel series exhibit tractable chemical properties for further development as potential therapeutic leads.
Copyright © 2015 Elsevier Ltd. All rights reserved.
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13 MeSH Terms
Preclinical Evaluation of 4-[18F]Fluoroglutamine PET to Assess ASCT2 Expression in Lung Cancer.
Hassanein M, Hight MR, Buck JR, Tantawy MN, Nickels ML, Hoeksema MD, Harris BK, Boyd K, Massion PP, Manning HC
(2016) Mol Imaging Biol 18: 18-23
MeSH Terms: Amino Acid Transport System ASC, Animals, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Colonic Neoplasms, ErbB Receptors, Female, Glutamine, Humans, Lung Neoplasms, Male, Mice, Nude, Minor Histocompatibility Antigens, Mutation, Positron-Emission Tomography, Xenograft Model Antitumor Assays
Show Abstract · Added September 30, 2015
PURPOSE - Alanine-serine-cysteine transporter 2 (ASCT2) expression has been demonstrated as a promising lung cancer biomarker. (2S,4R)-4-[(18)F]Fluoroglutamine (4-[(18)F]fluoro-Gln) positron emission tomography (PET) was evaluated in preclinical models of non-small cell lung cancer as a quantitative, non-invasive measure of ASCT2 expression.
PROCEDURES - In vivo microPET studies of 4-[(18)F]fluoro-Gln uptake were undertaken in human cell line xenograft tumor-bearing mice of varying ASCT2 levels, followed by a genetically engineered mouse model of epidermal growth factor receptor (EGFR)-mutant lung cancer. The relationship between a tracer accumulation and ASCT2 levels in tumors was evaluated by IHC and immunoblotting.
RESULT - 4-[(18)F]Fluoro-Gln uptake, but not 2-deoxy-2-[(18)F]fluoro-D-glucose, correlated with relative ASCT2 levels in xenograft tumors. In genetically engineered mice, 4-[(18)F]fluoro-Gln accumulation was significantly elevated in lung tumors, relative to normal lung and cardiac tissues.
CONCLUSIONS - 4-[(18)F]Fluoro-Gln PET appears to provide a non-invasive measure of ASCT2 expression. Given the potential of ASCT2 as a lung cancer biomarker, this and other tracers reflecting ASCT2 levels could emerge as precision imaging diagnostics in this setting.
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Targeting SLC1a5-mediated glutamine dependence in non-small cell lung cancer.
Hassanein M, Qian J, Hoeksema MD, Wang J, Jacobovitz M, Ji X, Harris FT, Harris BK, Boyd KL, Chen H, Eisenberg R, Massion PP
(2015) Int J Cancer 137: 1587-97
MeSH Terms: Amino Acid Transport System ASC, Animals, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Gene Knockdown Techniques, Glutamine, Humans, Lung Neoplasms, Mice, Minor Histocompatibility Antigens, Molecular Targeted Therapy, Prognosis, RNA, Small Interfering, Xenograft Model Antitumor Assays
Show Abstract · Added February 16, 2016
We previously elucidated the pleotropic role of solute carrier family A1 member 5 (SLC1A5) as the primary transporter of glutamine (Gln), a modulator of cell growth and oxidative stress in non-small cell lung cancer (NSCLC). The aim of our study was to evaluate SLC1A5 as a potential new therapeutic target and candidate biomarker predictive of survival and response to therapy. SLC1A5 targeting was examined in a panel of NSCLC and human bronchial cell lines by RNA interference and by a small molecular inhibitor, gamma-l-glutamyl-p-nitroanilide (GPNA). The effects of targeting SLC1A5 on cell growth, Gln uptake, ATP level, autophagy and cell death were examined. Inactivation of SLC1A5 genetically or pharmacologically decreased Gln consumption, inhibited cell growth, induced autophagy and apoptosis in a subgroup of NSCLC cell lines that overexpress SLC1A5. Targeting SLC1A5 function decreased tumor growth in NSCLC xenografts. A multivariate Cox proportional hazards analysis indicates that patients with increased SLC1A5 mRNA expression have significantly shorter overall survival (p = 0.01, HR = 1.24, 95% CI: 1.05-1.46), adjusted for age, gender, smoking history and disease stage. In an immunohistochemistry study on 207 NSCLC patients, SLC1A5 protein expression remained highly significant prognostic value in both univariate (p < 0.0001, HR = 1.45, 95% CI: 1.15-1.50) and multivariate analyses (p = 0.04, HR = 1.22, 95% CI: 1.01-1.31). These results position SLC1A5 as a new candidate prognostic biomarker for selective targeting of Gln-dependent NSCLC.
© 2015 UICC.
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