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Glutaminase

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https://www.readbyqxmd.com/read/28053289/glutaminolysis-gets-the-spotlight-in-cancer
#1
EDITORIAL
Daniel Herranz
News on: Inhibiting glutaminase in acute myeloid leukemia: Metabolic dependency of selected AML subtypes by Polina Matre et al. Oncotarget. 2016; 7(48): 79722-79735. doi: 10.18632/oncotarget.12944.
December 30, 2016: Oncotarget
https://www.readbyqxmd.com/read/28039459/a-novel-glutaminase-inhibitor-968-inhibits-the-migration-and-proliferation-of-non-small-cell-lung-cancer-cells-by-targeting-egfr-erk-signaling-pathway
#2
Tianyu Han, Meng Guo, Tingting Zhang, Mingxi Gan, Caifeng Xie, Jian-Bin Wang
Metabolic reprogramming is critical for cancer cell proliferation. Glutaminolysis which provides cancer cells with bioenergetics and intermediates for macromolecular synthesis have been intensively studied in recent years. Glutaminase C (GAC) is the first and rate-limiting enzyme in glutaminolysis and plays important roles in cancer initiation and progression. We previously screened a small molecule named 968, a specific inhibitor of GAC, to block the proliferation of human breast cancer cells. In this study, we found that 968 effectively inhibited NSCLC cell proliferation and migration and arrested G0/G1 phase of cell cycle...
December 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/28034771/lkb1-promotes-metabolic-flexibility-in-response-to-energy-stress
#3
Seth J Parker, Robert U Svensson, Ajit S Divakaruni, Austin E Lefebvre, Anne N Murphy, Reuben J Shaw, Christian M Metallo
The Liver Kinase B1 (LKB1) tumor suppressor acts as a metabolic energy sensor to regulate AMP-activated protein kinase (AMPK) signaling and is commonly mutated in various cancers, including non-small cell lung cancer (NSCLC). Tumor cells deficient in LKB1 may be uniquely sensitized to metabolic stresses, which may offer a therapeutic window in oncology. To address this question we have explored how functional LKB1 impacts the metabolism of NSCLC cells using (13)C metabolic flux analysis. Isogenic NSCLC cells expressing functional LKB1 exhibited higher flux through oxidative mitochondrial pathways compared to those deficient in LKB1...
December 26, 2016: Metabolic Engineering
https://www.readbyqxmd.com/read/28012058/glutamate-and-brain-glutaminases-in-drug-addiction
#4
Javier Márquez, José A Campos-Sandoval, Ana Peñalver, José M Matés, Juan A Segura, Eduardo Blanco, Francisco J Alonso, Fernando Rodríguez de Fonseca
Glutamate is the principal excitatory neurotransmitter in the central nervous system and its actions are related to the behavioral effects of psychostimulant drugs. In the last two decades, basic neuroscience research and preclinical studies with animal models are suggesting a critical role for glutamate transmission in drug reward, reinforcement, and relapse. Although most of the interest has been centered in post-synaptic glutamate receptors, the presynaptic synthesis of glutamate through brain glutaminases may also contribute to imbalances in glutamate homeostasis, a key feature of the glutamatergic hypothesis of addiction...
December 23, 2016: Neurochemical Research
https://www.readbyqxmd.com/read/28007957/molecular-portrait-of-metastasis-competent-circulating-tumor-cells-in-colon-cancer-reveals-the-crucial-role-of-genes-regulating-energy-metabolism-and-dna-repair
#5
Catherine Alix-Panabières, Laure Cayrefourcq, Thibault Mazard, Thierry Maudelonde, Eric Assenat, Said Assou
BACKGROUND: Unraveling the molecular mechanisms that regulate the biology of metastasis-competent circulating tumor cells (CTCs) is urgently needed to understand metastasis formation and tumor relapse. Our group previously established the first cell line (CTC-MCC-41) derived from metastasis-competent CTCs of a patient with colon cancer. METHODS: In this study, we analyzed the transcriptome of CTC-MCC-41 cells using Human Genome U133 Plus 2.0 microarrays with the aim of unraveling the molecular basis of their special features (stem cell properties and ability to initiate and support metastasis formation)...
December 22, 2016: Clinical Chemistry
https://www.readbyqxmd.com/read/27936490/combining-ancestral-sequence-reconstruction-with-protein-design-to-identify-an-interface-hotspot-in-a-key-metabolic-enzyme-complex
#6
Alexandra Holinski, Kristina Heyn, Rainer Merkl, Reinhard Sterner
It is important to identify hotspot residues that determine protein-protein interactions in interfaces of macromolecular complexes. We have applied a combination of ancestral sequence reconstruction and protein design to identify hotspots within imidazole glycerol phosphate synthase (ImGPS). ImGPS is a key metabolic enzyme complex, which links histidine and de novo purine biosynthesis and consists of the cyclase subunit HisF and the glutaminase subunit HisH. Initial fluorescence titration experiments showed that HisH from Zymomonas mobilis (zmHisH) binds with high affinity to the reconstructed HisF from the last universal common ancestor (LUCA-HisF) but not to HisF from Pyrobaculum arsenaticum (paHisF), which differ by 103 residues...
December 9, 2016: Proteins
https://www.readbyqxmd.com/read/27929535/dual-targeting-of-glutaminase-1-and-thymidylate-synthase-elicits-death-synergistically-in-nsclc
#7
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/27913195/breast-cancer-derived-extracellular-vesicles-stimulate-myofibroblast-differentiation-and-pro-angiogenic-behavior-of-adipose-stem-cells
#8
Young Hye Song, Christine Warncke, Sung Jin Choi, Siyoung Choi, Aaron E Chiou, Lu Ling, Han-Yuan Liu, Susan Daniel, Marc A Antonyak, Richard A Cerione, Claudia Fischbach
Adipose-derived stem cells (ASCs) are abundantly present in the mammary microenvironment and can promote breast cancer malignancy by differentiating into myofibroblasts. However, it remains largely unclear which role tumor-derived extracellular vesicles (TEVs) play in this process. Here, we used microfabricated, type I collagen-based 3-D tissue culture platforms to investigate the effect of breast cancer cell-derived TEVs on ASCs myofibroblast differentiation and consequential changes in extracellular matrix remodeling and vascular sprouting...
November 29, 2016: Matrix Biology: Journal of the International Society for Matrix Biology
https://www.readbyqxmd.com/read/27913184/tolerance-of-hyperammonemia-in-brain-of-heteropneustes-fossilis-is-supported-by-glutamate-glutamine-cycle
#9
Suman Mishra, Rajnikant Mishra
This report presents analysis of molecular switches associated with tolerance to hyperammonemia in Heteropneustes fossilis because it tolerates about 100-fold more ammonia than mammals. Brains of Heteropneustes fossilis exposed to 100mM ammonium chloride were dissected after Zero hour as control, 16h and 20h exposure. The status of neuron and glia were analysed by Golgi staining, Luxol Fast Blue, and Nissl's staining. The expression patterns of genes associated to homeostasis of neuron and glia, management of oxidative stress and inflammation, ammonia metabolism and brain derived neurotrophic factor were analysed through reverse-transcriptase-polymerase chain reaction...
November 29, 2016: Journal of Chemical Neuroanatomy
https://www.readbyqxmd.com/read/27911855/glutamine-and-glutaminolysis-are-required-for-efficient-replication-of-infectious-spleen-and-kidney-necrosis-virus-in-chinese-perch-brain-cells
#10
Xiaozhe Fu, Xianqin Hu, Ningqiu Li, Feifei Zheng, Xingxing Dong, Jing Duan, Qiang Lin, Jiagang Tu, Lijuan Zhao, Zhibin Huang, Jianguo Su, Li Lin
Viruses rely on host cellular metabolism for energy and macromolecule synthesis during their replication. Infectious spleen and kidney necrosis virus (ISKNV) causes significant economic losses in the Chinese perch (Siniperca chuatsi) industry worldwide. However, little is known about the relationship between ISKNV replication and cellular metabolism. Using transcriptomic analysis, we observed that glutamine metabolism in Chinese perch brain (CPB) cells is altered during ISKNV infection. Moreover, ISKNV replication was decreased in CPB cells cultured in the glutamine-depleted medium...
November 29, 2016: Oncotarget
https://www.readbyqxmd.com/read/27885676/effect%C3%A2-of%C3%A2-deamidation-induced%C3%A2-modification%C3%A2-on%C3%A2-umami%C3%A2-and%C3%A2-bitter%C3%A2-taste-of-wheat-gluten%C3%A2-hydrolysates
#11
Bo-Ye Liu, Ke-Xue Zhu, Xiao-Na Guo, Wei Peng, Hui-Ming Zhou
BACKGROUND: Bitter taste is the main limiting factor for various applications of protein hydrolysates. Frequently-used physicochemical methods for debittering protein hydrolysates came with some undesired side effects. Deamidation-induced modification method would be a very promising technique to improve the flavor of wheat gluten hydrolysates (WGHs). This study was designed to determine the effect of deamidation with certain enzymes or acid treatment on the chemical composition, bitterness and umami properties of WGHs...
November 25, 2016: Journal of the Science of Food and Agriculture
https://www.readbyqxmd.com/read/27885637/the-glutamate-glutamine-cycle-in-epilepsy
#12
Tore Eid, Shaun E Gruenbaum, Roni Dhaher, Tih-Shih W Lee, Yun Zhou, Niels Christian Danbolt
Epilepsy is a complex, multifactorial disease characterized by spontaneous recurrent seizures and an increased incidence of comorbid conditions such as anxiety, depression, cognitive dysfunction, and sudden unexpected death. About 70 million people worldwide are estimated to suffer from epilepsy, and up to one-third of all people with epilepsy are expected to be refractory to current medications. Development of more effective and specific antiepileptic interventions is therefore requisite. Perturbations in the brain's glutamate-glutamine cycle, such as increased extracellular levels of glutamate, loss of astroglial glutamine synthetase, and changes in glutaminase and glutamate dehydrogenase, are frequently encountered in patients with epilepsy...
2016: Advances in Neurobiology
https://www.readbyqxmd.com/read/27885632/glutamine-metabolism-in-gliomas
#13
Monika Szeliga, Jan Albrecht
By histological, morphological criteria, and malignancy, brain tumors are classified by WHO into grades I (most benign) to IV (highly malignant), and gliomas are the most frequently occurring class throughout the grades. Similar to peripheral tumors, the growth of glia-derived tumor cells largely depends on glutamine (Gln), which is vividly taken up by the cells, using mostly ASCT2 and SN1 as Gln carriers. Tumor growth-promoting effects of Gln are associated with its phosphate-activated glutaminase (GA) (specifically KGA)-mediated degradation to glutamate (Glu) and/or with its entry to the energy- and intermediate metabolite-generating pathways related to the tricarboxylic acid cycle...
2016: Advances in Neurobiology
https://www.readbyqxmd.com/read/27885629/glutaminases
#14
Javier Márquez, José M Matés, José A Campos-Sandoval
Mammalian glutaminases catalyze the stoichiometric conversion of L-glutamine to L-glutamate and ammonium ions. In brain, glutaminase is considered the prevailing pathway for synthesis of the neurotransmitter pool of glutamate. Besides neurotransmission, the products of glutaminase reaction also fulfill crucial roles in energy and metabolic homeostasis in mammalian brain. In the last years, new functional roles for brain glutaminases are being uncovered by using functional genomic and proteomic approaches. Glutaminases may act as multifunctional proteins able to perform different tasks: the discovery of multiple transcript variants in neurons and glial cells, novel extramitochondrial localizations, and isoform-specific proteininteracting partners strongly support possible moonlighting functions for these proteins...
2016: Advances in Neurobiology
https://www.readbyqxmd.com/read/27873132/mechanisms-of-excessive-extracellular-glutamate-accumulation-in-temporal-lobe-epilepsy
#15
Jan Albrecht, Magdalena Zielińska
There is compelling evidence that initiation and maintenance of epileptic seizures in temporal lobe epilepsy (TLE) is facilitated by excessive accumulation in the extracellular (perisynaptic) space of the excitatory neurotransmitter glutamate (Glu). This review discusses the mechanisms underlying this phenomenon. Glu released from neurons is taken up by astrocytes and activated there by glutamine synthetase (GS) to form glutamine (Gln) which upon entry to neurons is degraded back to Glu by phosphate-activated glutaminase (PAG): this chain of reactions has been defined as the glutamine/glutamate/cycle (GGC)...
November 21, 2016: Neurochemical Research
https://www.readbyqxmd.com/read/27872198/in-female-rat-heart-mitochondria-oophorectomy-results-in-loss-of-oxidative-phosphorylation
#16
Natalia Pavón, Alfredo Cabrera-Orefice, Juan Carlos Gallardo-Pérez, Cristina Uribe-Alvarez, Nadia A Rivero-Segura, Edgar Ricardo Vazquez-Martínez, Marco Cerbón, Eduardo Martínez-Abundis, Juan Carlos Torres-Narvaez, Raúl Martínez-Memije, Francisco-Javier Roldán-Gómez, Salvador Uribe-Carvajal
Oophorectomy in adult rats affected cardiac mitochondrial function. Progression of mitochondrial alterations was assessed at one, two and three months after surgery: at one month, very slight changes were observed, which increased at two and three months. Gradual effects included decrease in the rates of oxygen consumption and in respiratory uncoupling in the presence of complex I substrates, as well as compromised Ca(2+) buffering ability. Malondialdehyde concentration increased, whereas the ROS-detoxifying enzyme Mn(2+) superoxide dismutase (MnSOD) and aconitase lost activity...
February 2017: Journal of Endocrinology
https://www.readbyqxmd.com/read/27835669/the-glutaminase-1-inhibitor-968-enhances-dihydroartemisinin-mediated-antitumor-efficacy-in-hepatocellular-carcinoma-cells
#17
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/27831645/inhibition-of-mir-23-protects-myocardial-function-from-ischemia-reperfusion-injury-through-restoration-of-glutamine-metabolism
#18
Y Kou, W-T Zheng, Y-R Zhang
OBJECTIVE: Myocardial disorders caused by ischemia/reperfusion (IR) continue to be among the most frequent causes of debilitating disease and death. The contribution of cellular metabolism through the production of metabolic intermediates during IR has been increasingly investigated. MATERIALS AND METHODS: In this study, by using a rat IR injury model, we reported that the expression of microRNA miR-23 was induced by IR. In contrast, the glutamine metabolism was suppressed during IR...
October 2016: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/27830010/glutaminase-inhibitor-compound-968-inhibits-cell-proliferation-and-sensitizes-paclitaxel-in-ovarian-cancer
#19
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/27829138/targeting-stromal-glutamine-synthetase-in-tumors-disrupts-tumor-microenvironment-regulated-cancer-cell-growth
#20
Lifeng Yang, Abhinav Achreja, Tsz-Lun Yeung, Lingegowda S Mangala, Dahai Jiang, Cecil Han, Joelle Baddour, Juan C Marini, Joseph Ni, Ryuichi Nakahara, Stephen Wahlig, Lisa Chiba, Sun Hye Kim, Joshua Morse, Sunila Pradeep, Archana Sidalaghatta Nagaraja, Monika Haemmerle, Noh Kyunghee, Mathew Derichsweiler, Thomas Plackemeier, Imelda Mercado-Uribe, Gabriel Lopez-Berestein, Tyler Moss, Prahlad T Ram, Jinsong Liu, Xiongbin Lu, Samuel C Mok, Anil K Sood, Deepak Nagrath
Reactive stromal cells are an integral part of tumor microenvironment (TME) and interact with cancer cells to regulate their growth. Although targeting stromal cells could be a viable therapy to regulate the communication between TME and cancer cells, identification of stromal targets that make cancer cells vulnerable has remained challenging and elusive. Here, we identify a previously unrecognized mechanism whereby metabolism of reactive stromal cells is reprogrammed through an upregulated glutamine anabolic pathway...
November 8, 2016: Cell Metabolism
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