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https://www.readbyqxmd.com/read/28659375/role-of-glutamine-and-interlinked-asparagine-metabolism-in-vessel-formation
#1
Hongling Huang, Saar Vandekeere, Joanna Kalucka, Laura Bierhansl, Annalisa Zecchin, Ulrike Brüning, Asjad Visnagri, Nadira Yuldasheva, Jermaine Goveia, Bert Cruys, Katleen Brepoels, Sabine Wyns, Stephen Rayport, Bart Ghesquière, Stefan Vinckier, Luc Schoonjans, Richard Cubbon, Mieke Dewerchin, Guy Eelen, Peter Carmeliet
Endothelial cell (EC) metabolism is emerging as a regulator of angiogenesis, but the precise role of glutamine metabolism in ECs is unknown. Here, we show that depriving ECs of glutamine or inhibiting glutaminase 1 (GLS1) caused vessel sprouting defects due to impaired proliferation and migration, and reduced pathological ocular angiogenesis. Inhibition of glutamine metabolism in ECs did not cause energy distress, but impaired tricarboxylic acid (TCA) cycle anaplerosis, macromolecule production, and redox homeostasis...
June 28, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28624534/glutaminase-c-overexpression-in-the-brain-induces-learning-deficits-synaptic-dysfunctions-and-neuroinflammation-in-mice
#2
Yi Wang, Yuju Li, Runze Zhao, Beiqing Wu, Blaise Lanoha, Zenghan Tong, Justin Peer, Jianhui Liu, Huangui Xiong, Yunlong Huang, Jialin Zheng
Glutaminolysis, a metabolic process that converts glutamine to glutamate, is particularly important for the central nervous system since glutamate is the major transmitter of excitatory synapses. Glutaminase is the mitochondrial enzyme that catalyzes the first step of glutaminolysis. Two genes encode at least four isoforms of glutaminase in humans. GLS1 gene encodes isoforms kidney-type glutaminase and glutaminase C (GAC) through alternative splicing, whereas GLS2 gene encodes liver-type glutaminase isoforms...
June 14, 2017: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/28609101/design-synthesis-and-evaluation-of-thiazolidine-2-4-dione-derivatives-as-a-novel-class-of-glutaminase-inhibitors
#3
Teng-Kuang Yeh, Ching-Chuan Kuo, Yue-Zhi Lee, Yi-Yu Ke, Kuang-Feng Chu, Hsing-Yu Hsu, Hsin-Yu Chang, Yu-Wei Liu, Jen-Shin Song, Cheng-Wei Yang, Li-Mei Lin, Manwu Sun, Szu-Huei Wu, Po-Chu Kuo, Chuan Shih, Chiung-Tong Chen, Lun Kelvin Tsou, Shiow-Ju Lee
Humans have two glutaminase genes, GLS (GLS1) and GLS2, each of which has two alternative transcripts: the kidney isoform (KGA) and glutaminase C (GAC) for GLS, and the liver isoform (LGA) and glutaminase B (GAB) for GLS2. Initial hit compound (Z)-5-((1-(4-bromophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)methylene)thiazolidine-2,4-dione (2), a thiazolidine-2,4-dione, was obtained from a high throughput screening of 40 000 compounds against KGA. Subsequently, a series of thiazolidine-2,4-dione derivatives was synthesized...
June 29, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28599272/pre-clinical-pharmacology-of-azd3965-a-selective-inhibitor-of-mct1-dlbcl-nhl-and-burkitt-s-lymphoma-anti-tumor-activity
#4
Nicola J Curtis, Lorraine Mooney, Lorna Hopcroft, Filippos Michopoulos, Nichola Whalley, Haihong Zhong, Clare Murray, Armelle Logie, Mitchell Revill, Kate F Byth, Amanda D Benjamin, Mike A Firth, Stephen Green, Paul D Smith, Susan E Critchlow
Tumors frequently display a glycolytic phenotype with increased flux through glycolysis and concomitant synthesis of lactate. To maintain glycolytic flux and prevent intracellular acidification, tumors efflux lactate via lactate transporters (MCT1-4). Inhibitors of lactate transport have the potential to inhibit glycolysis and tumor growth. We developed a small molecule inhibitor of MCT1 (AZD3965) and assessed its activity across a panel of cell lines. We explored its antitumor activity as monotherapy and in combination with doxorubicin or rituximab...
May 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28571744/kr-pok-zbtb7c-regulates-cancer-cell-proliferation-through-glutamine-metabolism
#5
Man-Wook Hur, Jae-Hyeon Yoon, Min-Young Kim, Hyeonseok Ko, Bu-Nam Jeon
Kr-POK (ZBTB7c) is a kidney cancer-related POK transcription factor that not only represses transcription of CDKN1A but also increases expression of FASN. However, precisely how Kr-POK affects cell metabolism by controlling gene expression in response to an energy source in rapidly proliferating cells remains unknown. In this study, we characterized the molecular and functional features of Kr-POK in the context of tumor growth and glutamine metabolism. We found that cells expressing Kr-POK shRNA exhibited more severe cell death than control cells in glucose-deprived medium, and that knockdown of Kr-POK decreased glutamine uptake...
May 30, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28498807/knockdown-of-pkm2-and-gls1-expression-can-significantly-reverse-oxaliplatin-resistance-in-colorectal-cancer-cells
#6
Wei-Qun Lu, Ying-Ying Hu, Xiao-Ping Lin, Wei Fan
Clinical treatment for colorectal cancer (CRC) thus far encounters a huge challenge due to oxaliplatin-resistance. As crucial rate-limiting enzymes in aerobic glycolysis and glutaminolysis, pyruvate kinase M2 type (PKM2) and kidney-type glutaminase (GLS1) are proposed to carry important implications in colorectal carcinogenesis and drug-resistance. This study aimed to explore the possible association of oxaliplatin-resistance with aerobic glycolysis/glutaminolysis indexed by PKM2/GLS1 expression. PKM2 and GLS1 expression was quantified by polymerase chain reaction (PCR) and Western blot techniques in CRC cell lines...
July 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28399896/glutaminase-1-plays-a-key-role-in-the-cell-growth-of-fibroblast-like-synoviocytes-in-rheumatoid-arthritis
#7
Soshi Takahashi, Jun Saegusa, Sho Sendo, Takaichi Okano, Kengo Akashi, Yasuhiro Irino, Akio Morinobu
BACKGROUND: The recent findings of cancer-specific metabolic changes, including increased glucose and glutamine consumption, have provided new therapeutic targets for consideration. Fibroblast-like synoviocytes (FLS) from rheumatoid arthritis (RA) patients exhibit several tumor cell-like characteristics; however, the role of glucose and glutamine metabolism in the aberrant proliferation of these cells is unclear. Here, we evaluated the role of these metabolic pathways in RA-FLS proliferation and in autoimmune arthritis in SKG mice...
April 11, 2017: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/28346230/glutaminase-and-poly-adp-ribose-polymerase-inhibitors-suppress-pyrimidine-synthesis-and-vhl-deficient-renal-cancers
#8
Arimichi Okazaki, Paulo A Gameiro, Danos Christodoulou, Laura Laviollette, Meike Schneider, Frances Chaves, Anat Stemmer-Rachamimov, Stephanie A Yazinski, Richard Lee, Gregory Stephanopoulos, Lee Zou, Othon Iliopoulos
Many cancer-associated mutations that deregulate cellular metabolic responses to hypoxia also reprogram carbon metabolism to promote utilization of glutamine. In renal cell carcinoma (RCC), cells deficient in the von Hippel-Lindau (VHL) tumor suppressor gene use glutamine to generate citrate and lipids through reductive carboxylation (RC) of α-ketoglutarate (αKG). Glutamine can also generate aspartate, the carbon source for pyrimidine biosynthesis, and glutathione for redox balance. Here we have shown that VHL-/- RCC cells rely on RC-derived aspartate to maintain de novo pyrimidine biosynthesis...
May 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28190586/increased-expression-of-glutaminase-in-osteoblasts-promotes-macrophage-recruitment-in-periapical-lesions
#9
Kuo-Liang Hou, Sze-Kwan Lin, Sang-Heng Kok, Han-Wei Wang, Eddie Hsiang-Hua Lai, Chi-Yuan Hong, Hsiang Yang, Juo-Song Wang, Li-Deh Lin, Jenny Zwei-Chieng Chang
INTRODUCTION: Recently, we have shown that tissue hypoxia stimulates the progression of periapical lesions by up-regulating glycolysis-dependent apoptosis of osteoblasts. Other facets of hypoxia-induced metabolic reprogramming in disease pathogenesis require further investigation. In this study, we examined the connection between hypoxia-augmented glutamine catabolism in osteoblasts and the development of periapical lesions. METHODS: Primary human osteoblasts were cultured under hypoxia...
April 2017: Journal of Endodontics
https://www.readbyqxmd.com/read/27929535/dual-targeting-of-glutaminase-1-and-thymidylate-synthase-elicits-death-synergistically-in-nsclc
#10
Jae-Seon Lee, Joon H Kang, Seon-Hyeong Lee, Dongwan Hong, Jaekyoung Son, Kyeong M Hong, Jaewhan Song, Soo-Youl Kim
Glutaminase 1 (GLS1) expression is increased in non-small cell lung cancer (NSCLC). GLS1 knockdown using siRNA or inhibition using bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) induced cell cycle arrest with significant reduction of ATP level while levels of reactive oxygen species or glutathione were not affected in NSCLC cell lines. Recently we found that NSCLC significantly depends on cytosol NADH for ATP production. GLS1 remarkably contributes to ATP production through transferring cytosolic NADH into mitochondria via malate-aspartate shuttle by supply of glutamate in NSCLC...
December 8, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27902968/selenite-inhibits-glutamine-metabolism-and-induces-apoptosis-by-regulating-gls1-protein-degradation-via-apc-c-cdh1-pathway-in-colorectal-cancer-cells
#11
Junzhang Zhao, Rui Zhou, Kaiyuan Hui, Yang Yang, QiuYue Zhang, Yali Ci, Lei Shi, Caimin Xu, Fang Huang, Yu Hu
Glutaminolysis is important for metabolism and biosynthesis of cancer cells, and GLS is essential in the process. Selenite is widely regarded as a chemopreventive agent against cancer risk. Emerging evidence suggests that it also has chemotherapeutic potential in various cancer types, but the mechanism remains elusive. We demonstrate for the first time that supranutritional dose of selenite suppresses glutaminolysis by promoting GLS1 protein degradation and apoptosis. Mechanistically, selenite promotes association of APC/C-CDH1 with GLS1 and leads to GLS1 degradation by ubiquitination, this process is related to induction of PTEN expression...
March 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/27835669/the-glutaminase-1-inhibitor-968-enhances-dihydroartemisinin-mediated-antitumor-efficacy-in-hepatocellular-carcinoma-cells
#12
Diancheng Wang, Gang Meng, Meihong Zheng, Yonghui Zhang, Aiping Chen, Junhua Wu, Jiwu Wei
Reprogrammed metabolism and redox homeostasis are potential targets of cancer therapy. Our previous study demonstrated that the kidney form of glutaminase (GLS1) is highly expressed in hepatocellular carcinoma (HCC) cells and can be used as a target for effective anticancer therapy. Dihydroartemisinin (DHA) increases intracellular reactive oxygen species (ROS) levels leading to cytotoxicity in cancer cells. However, the heterogeneity of cancer cells often leads to differing responses to oxidative lesions. For instance, cancer cells with high ratio of GSH/GSSG, a critical ROS scavenger, are resistant to ROS-induced cytotoxicity...
2016: PloS One
https://www.readbyqxmd.com/read/27830010/glutaminase-inhibitor-compound-968-inhibits-cell-proliferation-and-sensitizes-paclitaxel-in-ovarian-cancer
#13
Lingqin Yuan, Xiugui Sheng, Leslie H Clark, Lu Zhang, Hui Guo, Hannah M Jones, Adam K Willson, Paola A Gehrig, Chunxiao Zhou, Victoria L Bae-Jump
Our overall goal was to investigate the anti-tumor activity of the glutaminase 1 (GLS1) Inhibitor compound 968 in ovarian cancer cells. The human ovarian cancer cell lines, HEY, SKOV3 and IGROV-1 were used. Cell proliferation was assessed by MTT assay after treatment with compound 968. Cell cycle progression and Annexin V expression were evaluated using Cellometer. Western blotting was performed to determine changes in GLS1, cellular stress and cell cycle checkpoints. Reactive oxygen species (ROS) and glutamate dehydrogenase (GDH) activity were assessed by ELISA assay...
2016: American Journal of Translational Research
https://www.readbyqxmd.com/read/27806325/inhibiting-glutaminase-in-acute-myeloid-leukemia-metabolic-dependency-of-selected-aml-subtypes
#14
Polina Matre, Juliana Velez, Rodrigo Jacamo, Yuan Qi, Xiaoping Su, Tianyu Cai, Steven M Chan, Alessia Lodi, Shannon R Sweeney, Helen Ma, Richard Eric Davis, Natalia Baran, Torsten Haferlach, Xiaohua Su, Elsa Renee Flores, Doriann Gonzalez, Sergej Konoplev, Ismael Samudio, Courtney DiNardo, Ravi Majeti, Aaron D Schimmer, Weiqun Li, Taotao Wang, Stefano Tiziani, Marina Konopleva
Metabolic reprogramming has been described as a hallmark of transformed cancer cells. In this study, we examined the role of the glutamine (Gln) utilization pathway in acute myeloid leukemia (AML) cell lines and primary AML samples. Our results indicate that a subset of AML cell lines is sensitive to Gln deprivation. Glutaminase (GLS) is a mitochondrial enzyme that catalyzes the conversion of Gln to glutamate. One of the two GLS isoenzymes, GLS1 is highly expressed in cancer and encodes two different isoforms: kidney (KGA) and glutaminase C (GAC)...
November 29, 2016: Oncotarget
https://www.readbyqxmd.com/read/27793929/inhibition-of-glutaminolysis-inhibits-cell-growth-via-down-regulating-mtorc1-signaling-in-lung-squamous-cell-carcinoma
#15
Xulu Ye, Qiliang Zhou, Yoshifumi Matsumoto, Masato Moriyama, Shun Kageyama, Masaaki Komatsu, Seijiro Satoh, Masanori Tsuchida, Yasuo Saijo
BACKGROUND/AIM: Inhibition of glutaminolysis has been reported as a promising therapeutic strategy to target several solid carcinomas. We aimed to investigate the effects of glutaminolysis on cell proliferation in lung squamous cell carcinoma cell lines and to explore the potential of targeting glutaminolysis as an anticancer strategy. MATERIALS AND METHODS: Glutamine (Gln) dependence was assessed in six lung squamous cell carcinoma cell lines. Cell proliferation, mammalian target of rapamycin complex 1 (mTORC1) activity and the induction of autophagy were assessed after inhibition of glutaminolysis via Gln depletion or glutaminase (GLS) inhibition...
2016: Anticancer Research
https://www.readbyqxmd.com/read/27548520/vascular-stiffness-mechanoactivates-yap-taz-dependent-glutaminolysis-to-drive-pulmonary-hypertension
#16
Thomas Bertero, William M Oldham, Katherine A Cottrill, Sabrina Pisano, Rebecca R Vanderpool, Qiujun Yu, Jingsi Zhao, Yiyin Tai, Ying Tang, Ying-Yi Zhang, Sofiya Rehman, Masataka Sugahara, Zhi Qi, John Gorcsan, Sara O Vargas, Rajan Saggar, Rajeev Saggar, W Dean Wallace, David J Ross, Kathleen J Haley, Aaron B Waxman, Victoria N Parikh, Teresa De Marco, Priscilla Y Hsue, Alison Morris, Marc A Simon, Karen A Norris, Cedric Gaggioli, Joseph Loscalzo, Joshua Fessel, Stephen Y Chan
Dysregulation of vascular stiffness and cellular metabolism occurs early in pulmonary hypertension (PH). However, the mechanisms by which biophysical properties of the vascular extracellular matrix (ECM) relate to metabolic processes important in PH remain undefined. In this work, we examined cultured pulmonary vascular cells and various types of PH-diseased lung tissue and determined that ECM stiffening resulted in mechanoactivation of the transcriptional coactivators YAP and TAZ (WWTR1). YAP/TAZ activation modulated metabolic enzymes, including glutaminase (GLS1), to coordinate glutaminolysis and glycolysis...
September 1, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27467144/t-helper-cell-activation-and-expansion-is-sensitive-to-glutaminase-inhibition-under-both-hypoxic-and-normoxic-conditions
#17
Zeynep Sener, Fritjof H Cederkvist, Roman Volchenkov, Halvor L Holen, Bjørn S Skålhegg
Immune responses often take place where nutrients and O2 availability are limited. This has an impact on T cell metabolism and influences activation and effector functions. T cell proliferation and expansion are associated with increased consumption of glutamine which is needed in a number of metabolic pathways and regulate various physiological processes. The first step in endogenous glutamine metabolism is reversible and is regulated by glutaminase (GLS1 and GLS2) and glutamine synthase (GLUL). There are two isoforms of GLS1, Kidney type glutaminase (KGA) and Glutaminase C (GAC)...
2016: PloS One
https://www.readbyqxmd.com/read/27462778/pdha1-gene-knockout-in-prostate-cancer-cells-results-in-metabolic-reprogramming-towards-greater-glutamine-dependence
#18
Yaqing Li, Xiaoran Li, Xiaoli Li, Yali Zhong, Yasai Ji, Dandan Yu, Mingzhi Zhang, Jian-Guo Wen, Hongquan Zhang, Mariusz Adam Goscinski, Jahn M Nesland, Zhenhe Suo
Alternative pathways of metabolism endowed cancer cells with metabolic stress. Inhibiting the related compensatory pathways might achieve synergistic anticancer results. This study demonstrated that pyruvate dehydrogenase E1α gene knockout (PDHA1 KO) resulted in alterations in tumor cell metabolism by rendering the cells with increased expression of glutaminase1 (GLS1) and glutamate dehydrogenase1 (GLUD1), leading to an increase in glutamine-dependent cell survival. Deprivation of glutamine induced cell growth inhibition, increased reactive oxygen species and decreased ATP production...
August 16, 2016: Oncotarget
https://www.readbyqxmd.com/read/27447554/expression-of-glutamine-metabolism-related-proteins-in-thyroid-cancer
#19
Hye Min Kim, Yu Kyung Lee, Ja Seung Koo
PURPOSE: This study aimed to investigate the expression of glutamine metabolism-related protein in tumor and stromal compartments among the histologic subtypes of thyroid cancer. RESULTS: GLS1 and GDH expression in tumor and stromal compartments were the highest in AC than in other subtypes. Tumoral ASCT2 expression was higher in MC but lower in FC (p < 0.001). In PTC, tumoral GLS1 and tumoral GDH expression was higher in the conventional type than in the follicular variant (p = 0...
August 16, 2016: Oncotarget
https://www.readbyqxmd.com/read/27411920/inhibition-of-the-oxidative-stress-induced-mir-23a-protects-the-human-retinal-pigment-epithelium-rpe-cells-from-apoptosis-through-the-upregulation-of-glutaminase-and-glutamine-uptake
#20
Dan-Dan Li, Bin-Wu Zhong, Hai-Xia Zhang, Hong-Yan Zhou, Jie Luo, Yang Liu, Gui-Chun Xu, Chun-Sheng Luan, Jun Fang
The degeneration of retinal pigment epithelium (RPE) cells in the sub retinal pigment epithelial space and choroid is an initial pathological characteristic for the age-related macular degeneration which is the leading cause of severe vision loss in old people. Moreover, oxidative stress is implicated as a major inducer of RPE cell death. Here, we assessed the correlation between the H2O2-induced RPE cell death and glutamine metabolism. We found under low glutamine supply (20 %), the ARPE-19 cells were more susceptive to H2O2-induced apoptosis...
October 2016: Molecular Biology Reports
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