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Pesquisa : D08.811.277.087.483 [Categoria DeCS]
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  1 / 1719 MEDLINE  
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[PMID]:29107960
[Au] Autor:Tran TQ; Ishak Gabra MB; Lowman XH; Yang Y; Reid MA; Pan M; O'Connor TR; Kong M
[Ad] Endereço:Department of Cancer Biology, Beckman Research Institute of the City of Hope, Duarte, California, United States of America.
[Ti] Título:Glutamine deficiency induces DNA alkylation damage and sensitizes cancer cells to alkylating agents through inhibition of ALKBH enzymes.
[So] Source:PLoS Biol;15(11):e2002810, 2017 Nov.
[Is] ISSN:1545-7885
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Driven by oncogenic signaling, glutamine addiction exhibited by cancer cells often leads to severe glutamine depletion in solid tumors. Despite this nutritional environment that tumor cells often experience, the effect of glutamine deficiency on cellular responses to DNA damage and chemotherapeutic treatment remains unclear. Here, we show that glutamine deficiency, through the reduction of alpha-ketoglutarate, inhibits the AlkB homolog (ALKBH) enzymes activity and induces DNA alkylation damage. As a result, glutamine deprivation or glutaminase inhibitor treatment triggers DNA damage accumulation independent of cell death. In addition, low glutamine-induced DNA damage is abolished in ALKBH deficient cells. Importantly, we show that glutaminase inhibitors, 6-Diazo-5-oxo-L-norleucine (DON) or CB-839, hypersensitize cancer cells to alkylating agents both in vitro and in vivo. Together, the crosstalk between glutamine metabolism and the DNA repair pathway identified in this study highlights a potential role of metabolic stress in genomic instability and therapeutic response in cancer.
[Mh] Termos MeSH primário: Enzimas AlkB/antagonistas & inibidores
Antineoplásicos Alquilantes/uso terapêutico
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Inibidores Enzimáticos/uso terapêutico
Glutaminase/antagonistas & inibidores
Proteínas de Neoplasias/antagonistas & inibidores
Neoplasias/tratamento farmacológico
[Mh] Termos MeSH secundário: Enzimas AlkB/genética
Enzimas AlkB/metabolismo
Homólogo AlkB 3 da Dioxigenase Dependente de alfa-Cetoglutarato/antagonistas & inibidores
Homólogo AlkB 3 da Dioxigenase Dependente de alfa-Cetoglutarato/genética
Homólogo AlkB 3 da Dioxigenase Dependente de alfa-Cetoglutarato/metabolismo
Alquilação/efeitos dos fármacos
Animais
Antineoplásicos Alquilantes/farmacologia
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia
Apoptose/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Dano ao DNA
Inibidores Enzimáticos/farmacologia
Glutaminase/metabolismo
Seres Humanos
Masculino
Camundongos
Camundongos Nus
Proteínas de Neoplasias/genética
Proteínas de Neoplasias/metabolismo
Neoplasias/metabolismo
Neoplasias/patologia
Interferência de RNA
Distribuição Aleatória
Carga Tumoral/efeitos dos fármacos
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents, Alkylating); 0 (Enzyme Inhibitors); 0 (Neoplasm Proteins); EC 1.14.11.- (ALKBH3 protein, human); EC 1.14.11.- (AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase); EC 1.14.11.33 (AlkB Enzymes); EC 3.5.1.2 (Glutaminase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171119
[Lr] Data última revisão:
171119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171107
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pbio.2002810


  2 / 1719 MEDLINE  
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[PMID]:28950000
[Au] Autor:Lampa M; Arlt H; He T; Ospina B; Reeves J; Zhang B; Murtie J; Deng G; Barberis C; Hoffmann D; Cheng H; Pollard J; Winter C; Richon V; Garcia-Escheverria C; Adrian F; Wiederschain D; Srinivasan L
[Ad] Endereço:Oncology, Sanofi, Cambridge, MA, United States of America.
[Ti] Título: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.
[So] Source:PLoS One;12(9):e0185092, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Tumor cells display fundamental changes in metabolism and nutrient uptake in order to utilize additional nutrient sources to meet their enhanced bioenergetic requirements. Glutamine (Gln) is one such nutrient that is rapidly taken up by tumor cells to fulfill this increased metabolic demand. A vital step in the catabolism of glutamine is its conversion to glutamate by the mitochondrial enzyme glutaminase (GLS). This study has identified GLS a potential therapeutic target in breast cancer, specifically in the basal subtype that exhibits a deregulated glutaminolysis pathway. Using inducible shRNA mediated gene knockdown, we discovered that loss of GLS function in triple-negative breast cancer (TNBC) cell lines with a deregulated glutaminolysis pathway led to profound tumor growth inhibition in vitro and in vivo. GLS knockdown had no effect on growth and metabolite levels in non-TNBC cell lines. We rescued the anti-tumor effect of GLS knockdown using shRNA resistant cDNAs encoding both GLS isoforms and by addition of an α-ketoglutarate (αKG) analog thus confirming the critical role of GLS in TNBC. Pharmacological inhibition of GLS with the small molecule inhibitor CB-839 reduced cell growth and led to a decrease in mammalian target of rapamycin (mTOR) activity and an increase in the stress response pathway driven by activating transcription factor 4 (ATF4). Finally, we found that GLS inhibition synergizes with mTOR inhibition, which introduces the possibility of a novel therapeutic strategy for TNBC. Our study revealed that GLS is essential for the survival of TNBC with a deregulated glutaminolysis pathway. The synergistic activity of GLS and mTOR inhibitors in TNBC cell lines suggests therapeutic potential of this combination for the treatment of vulnerable subpopulations of TNBC.
[Mh] Termos MeSH primário: Glutaminase/metabolismo
Glutamina/metabolismo
Serina-Treonina Quinases TOR/antagonistas & inibidores
Neoplasias de Mama Triplo Negativas/enzimologia
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Feminino
Seres Humanos
Neoplasias de Mama Triplo Negativas/metabolismo
Neoplasias de Mama Triplo Negativas/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0RH81L854J (Glutamine); EC 2.7.1.1 (MTOR protein, human); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 3.5.1.2 (Glutaminase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170927
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0185092


  3 / 1719 MEDLINE  
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[PMID]:28916328
[Au] Autor:Del Pino J; Moyano P; Díaz GG; Anadon MJ; Diaz MJ; García JM; Lobo M; Pelayo A; Sola E; Frejo MT
[Ad] Endereço:Department of Toxicology and Pharmacology, Veterinary School, Complutense University of Madrid, 28040 Madrid, Spain. Electronic address: jdelpino@pdi.ucm.es.
[Ti] Título:Primary hippocampal neuronal cell death induction after acute and repeated paraquat exposures mediated by AChE variants alteration and cholinergic and glutamatergic transmission disruption.
[So] Source:Toxicology;390:88-99, 2017 Sep 01.
[Is] ISSN:1879-3185
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Paraquat (PQ) is a widely used non-selective contact herbicide shown to produce memory and learning deficits after acute and repeated exposure similar to those induced in Alzheimer's disease (AD). However, the complete mechanisms through which it induces these effects are unknown. On the other hand, cholinergic and glutamatergic systems, mainly in the hippocampus, are involved on learning, memory and cell viability regulation. An alteration of hippocampal cholinergic or glutamatergic transmissions or neuronal cell loss may induce these effects. In this regard, it has been suggested that PQ may induce cell death and affect cholinergic and glutamatergic transmission, which alteration could produce neuronal loss. According to these data, we hypothesized that PQ could induce hippocampal neuronal loss through cholinergic and glutamatergic transmissions alteration. To prove this hypothesis, we evaluated in hippocampal primary cell culture, the PQ toxic effects after 24h and 14 consecutive days exposure on neuronal viability and the cholinergic and glutamatergic mechanisms related to it. This study shows that PQ impaired acetylcholine levels and induced AChE inhibition and increased CHT expression only after 14days exposure, which suggests that acetylcholine levels alteration could be mediated by these actions. PQ also disrupted glutamate levels through induction of glutaminase activity. In addition, PQ induced, after 24h and 14days exposure, cell death on hippocampal neurons that was partially mediated by AChE variants alteration and cholinergic and gultamatergic transmissions disruption. Our present results provide new view of the mechanisms contributing to PQ neurotoxicity and may explain cognitive dysfunctions observed after PQ exposure.
[Mh] Termos MeSH primário: Acetilcolina/metabolismo
Acetilcolinesterase/metabolismo
Ácido Glutâmico/metabolismo
Herbicidas/toxicidade
Hipocampo/efeitos dos fármacos
Neurônios/efeitos dos fármacos
Paraquat/toxicidade
Transmissão Sináptica/efeitos dos fármacos
[Mh] Termos MeSH secundário: Acetilcolinesterase/genética
Animais
Comportamento Animal/efeitos dos fármacos
Morte Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Células Cultivadas
Colina O-Acetiltransferase/genética
Colina O-Acetiltransferase/metabolismo
Cognição/efeitos dos fármacos
Relação Dose-Resposta a Droga
Proteínas Ligadas por GPI/genética
Proteínas Ligadas por GPI/metabolismo
Idade Gestacional
Glutaminase/genética
Glutaminase/metabolismo
Hipocampo/enzimologia
Hipocampo/patologia
Hipocampo/fisiopatologia
Proteínas de Membrana Transportadoras/genética
Proteínas de Membrana Transportadoras/metabolismo
Neurônios/enzimologia
Neurônios/patologia
Cultura Primária de Células
Interferência de RNA
Ratos Wistar
Fatores de Tempo
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (GPI-Linked Proteins); 0 (Herbicides); 0 (Membrane Transport Proteins); 0 (choline transporter); 3KX376GY7L (Glutamic Acid); EC 2.3.1.6 (Choline O-Acetyltransferase); EC 3.1.1.7 (Acetylcholinesterase); EC 3.1.1.7 (Ache protein, rat); EC 3.5.1.2 (Glutaminase); N9YNS0M02X (Acetylcholine); PLG39H7695 (Paraquat)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171023
[Lr] Data última revisão:
171023
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170917
[St] Status:MEDLINE


  4 / 1719 MEDLINE  
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[PMID]:28813436
[Au] Autor:Jesuraj SAV; Sarker MMR; Ming LC; Praya SMJ; Ravikumar M; Wui WT
[Ad] Endereço:Centre for Pharmaceutical Sciences, JNT University, Kukatpally, Hyderabad, Telengana State, India.
[Ti] Título:Enhancement of the production of L-glutaminase, an anticancer enzyme, from Aeromonas veronii by adaptive and induced mutation techniques.
[So] Source:PLoS One;12(8):e0181745, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Microbial anti-cancer enzymes have been proven to be effective and economical agents for cancer treatment. Aeromonas veronii has been identified as a microorganism with the potential to produce L-glutaminase, an anticancer agent effective against acute lymphocytic leukaemia. In this study, a selective medium of Aeromonas veronii was used to culture the microorganism. Strain improvement was done by adaptive and induced mutational techniques. A selective minimal agar media was incorporated for the growth of the strain which further supports adaptive mutation. Strains were also UV-irradiated and successively treated with N-methyl-N'-nitro-N-nitrosoguanidine to find a resilient strain capable of producing L-glutaminase efficiently. The Plackett-Burman design and central composite designs were used to screen and optimize additional carbon and nitrogen sources. Adaptive mutation resulted in promising yield improvements compared to native strain (P<0.001). The mean yield of 30 treated colonies from the induced mutation was significantly increased compared to the non-induced strain (P< 0.001). The economically feasible statistical designs were found to reinforce each other in order to maximize the yield of the enzyme. The interactions of nutrient factors were understood from the 3D response surface plots. The model was found to be a perfect fit in terms of maximizing enzyme yield, with the productivity improving at every stage to a fourfold output of enzyme (591.11 ±7.97 IU/mL) compared to the native strain (135±3.51 IU/mL).
[Mh] Termos MeSH primário: Adaptação Biológica
Aeromonas veronii/enzimologia
Aeromonas veronii/genética
Antineoplásicos/metabolismo
Glutaminase/biossíntese
Glutaminase/genética
Mutação
[Mh] Termos MeSH secundário: Análise de Variância
Sequência de Bases
Análise Mutacional de DNA
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); EC 3.5.1.2 (Glutaminase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170817
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0181745


  5 / 1719 MEDLINE  
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[PMID]:28759224
[Au] Autor:Nedelcovych MT; Tenora L; Kim BH; Kelschenbach J; Chao W; Hadas E; Jancarík A; Prchalová E; Zimmermann SC; Dash RP; Gadiano AJ; Garrett C; Furtmüller G; Oh B; Brandacher G; Alt J; Majer P; Volsky DJ; Rais R; Slusher BS
[Ti] Título:N-(Pivaloyloxy)alkoxy-carbonyl Prodrugs of the Glutamine Antagonist 6-Diazo-5-oxo-l-norleucine (DON) as a Potential Treatment for HIV Associated Neurocognitive Disorders.
[So] Source:J Med Chem;60(16):7186-7198, 2017 Aug 24.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Aberrant excitatory neurotransmission associated with overproduction of glutamate has been implicated in the development of HIV-associated neurocognitive disorders (HAND). The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON, 14) attenuates glutamate synthesis in HIV-infected microglia/macrophages, offering therapeutic potential for HAND. We show that 14 prevents manifestation of spatial memory deficits in chimeric EcoHIV-infected mice, a model of HAND. 14 is not clinically available, however, because its development was hampered by peripheral toxicities. We describe the synthesis of several substituted N-(pivaloyloxy)alkoxy-carbonyl prodrugs of 14 designed to circulate inert in plasma and be taken up and biotransformed to 14 in the brain. The lead prodrug, isopropyl 6-diazo-5-oxo-2-(((phenyl(pivaloyloxy)methoxy)carbonyl)amino)hexanoate (13d), was stable in swine and human plasma but liberated 14 in swine brain homogenate. When dosed systemically in swine, 13d provided a 15-fold enhanced CSF-to-plasma ratio and a 9-fold enhanced brain-to-plasma ratio relative to 14, opening a possible clinical path for the treatment of HAND.
[Mh] Termos MeSH primário: Aminocaproatos/farmacologia
Compostos Azo/farmacologia
Diazo-Oxo-Norleucina/farmacologia
Transtornos Neurocognitivos/tratamento farmacológico
Nootrópicos/farmacologia
Pró-Fármacos/farmacologia
[Mh] Termos MeSH secundário: Aminocaproatos/administração & dosagem
Aminocaproatos/síntese química
Animais
Compostos Azo/administração & dosagem
Compostos Azo/síntese química
Sangue/metabolismo
Encéfalo/metabolismo
Diazo-Oxo-Norleucina/administração & dosagem
Estabilidade de Medicamentos
Feminino
Ácido Glutâmico/metabolismo
Glutaminase/antagonistas & inibidores
Infecções por HIV/complicações
Seres Humanos
Masculino
Camundongos Endogâmicos C57BL
Transtornos Neurocognitivos/etiologia
Nootrópicos/administração & dosagem
Nootrópicos/síntese química
Pró-Fármacos/administração & dosagem
Pró-Fármacos/síntese química
Suínos
Carga Viral/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aminocaproates); 0 (Azo Compounds); 0 (Nootropic Agents); 0 (Prodrugs); 0 (isopropyl 6-diazo-5-oxo-2-(((phenyl(pivaloyloxy)methoxy)carbonyl)amino)hexanoate); 03J0H273KZ (Diazooxonorleucine); 3KX376GY7L (Glutamic Acid); EC 3.5.1.2 (Glutaminase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170801
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00966


  6 / 1719 MEDLINE  
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[PMID]:28659379
[Au] Autor:Kim B; Li J; Jang C; Arany Z
[Ad] Endereço:Department of Medicine, Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
[Ti] Título:Glutamine fuels proliferation but not migration of endothelial cells.
[So] Source:EMBO J;36(16):2321-2333, 2017 Aug 15.
[Is] ISSN:1460-2075
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Endothelial metabolism is a key regulator of angiogenesis. Glutamine metabolism in endothelial cells (ECs) has been poorly studied. We used genetic modifications and C tracing approaches to define glutamine metabolism in these cells. Glutamine supplies the majority of carbons in the tricyclic acid (TCA) cycle of ECs and contributes to lipid biosynthesis via reductive carboxylation. EC-specific deletion in mice of glutaminase, the initial enzyme in glutamine catabolism, markedly blunts angiogenesis. In cell culture, glutamine deprivation or inhibition of glutaminase prevents EC proliferation, but does not prevent cell migration, which relies instead on aerobic glycolysis. Without glutamine catabolism, there is near complete loss of TCA intermediates, with no compensation from glucose-derived anaplerosis. Mechanistically, addition of exogenous alpha-ketoglutarate replenishes TCA intermediates and rescues cellular growth, but simultaneously unveils a requirement for Rac1-dependent macropinocytosis to provide non-essential amino acids, including asparagine. Together, these data outline the dependence of ECs on glutamine for cataplerotic processes; the need for glutamine as a nitrogen source for generation of biomass; and the distinct roles of glucose and glutamine in EC biology.
[Mh] Termos MeSH primário: Movimento Celular
Proliferação Celular
Células Endoteliais/fisiologia
Glutamina/metabolismo
[Mh] Termos MeSH secundário: Isótopos de Carbono/metabolismo
Meios de Cultura/química
Deleção de Genes
Glutaminase/deficiência
Células Endoteliais da Veia Umbilical Humana
Seres Humanos
Marcação por Isótopo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carbon Isotopes); 0 (Culture Media); 0RH81L854J (Glutamine); EC 3.5.1.2 (Glutaminase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170828
[Lr] Data última revisão:
170828
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170630
[St] Status:MEDLINE
[do] DOI:10.15252/embj.201796436


  7 / 1719 MEDLINE  
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[PMID]:28659375
[Au] Autor:Huang H; Vandekeere S; Kalucka J; Bierhansl L; Zecchin A; Brüning U; Visnagri A; Yuldasheva N; Goveia J; Cruys B; Brepoels K; Wyns S; Rayport S; Ghesquière B; Vinckier S; Schoonjans L; Cubbon R; Dewerchin M; Eelen G; Carmeliet P
[Ad] Endereço:Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, Belgium.
[Ti] Título:Role of glutamine and interlinked asparagine metabolism in vessel formation.
[So] Source:EMBO J;36(16):2334-2352, 2017 Aug 15.
[Is] ISSN:1460-2075
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo: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. Only the combination of TCA cycle replenishment plus asparagine supplementation restored the metabolic aberrations and proliferation defect caused by glutamine deprivation. Mechanistically, glutamine provided nitrogen for asparagine synthesis to sustain cellular homeostasis. While ECs can take up asparagine, silencing asparagine synthetase (ASNS, which converts glutamine-derived nitrogen and aspartate to asparagine) impaired EC sprouting even in the presence of glutamine and asparagine. Asparagine further proved crucial in glutamine-deprived ECs to restore protein synthesis, suppress ER stress, and reactivate mTOR signaling. These findings reveal a novel link between endothelial glutamine and asparagine metabolism in vessel sprouting.
[Mh] Termos MeSH primário: Asparagina/metabolismo
Movimento Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Células Endoteliais/efeitos dos fármacos
Células Endoteliais/fisiologia
Glutamina/metabolismo
Neovascularização Fisiológica/efeitos dos fármacos
[Mh] Termos MeSH secundário: Meios de Cultura/química
Células Endoteliais/metabolismo
Glutaminase/metabolismo
Células Endoteliais da Veia Umbilical Humana
Seres Humanos
Redes e Vias Metabólicas
Neovascularização Patológica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Culture Media); 0RH81L854J (Glutamine); 7006-34-0 (Asparagine); EC 3.5.1.2 (GLS1 protein, human); EC 3.5.1.2 (Glutaminase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170828
[Lr] Data última revisão:
170828
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170630
[St] Status:MEDLINE
[do] DOI:10.15252/embj.201695518


  8 / 1719 MEDLINE  
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[PMID]:28609101
[Au] Autor:Yeh TK; Kuo CC; Lee YZ; Ke YY; Chu KF; Hsu HY; Chang HY; Liu YW; Song JS; Yang CW; Lin LM; Sun M; Wu SH; Kuo PC; Shih C; Chen CT; Tsou LK; Lee SJ
[Ad] Endereço:Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli 35053, Taiwan.
[Ti] Título:Design, Synthesis, and Evaluation of Thiazolidine-2,4-dione Derivatives as a Novel Class of Glutaminase Inhibitors.
[So] Source:J Med Chem;60(13):5599-5612, 2017 Jul 13.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo: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. Most of these were found to inhibit KGA and GAC with comparable activities, were less potent inhibitors of GAB, and were moderately selective for GLS1 over GLS2. The relationships between chemical structure, activity, and selectivity were investigated. The lead compounds obtained were found to (1) offer in vitro cellular activities for inhibiting cell growth, clonogenicity, and cellular glutamate production, (2) exhibit high concentrations of exposure in plasma by a pharmacokinetic study, and (3) reduce the tumor size of xenografted human pancreatic AsPC-1 carcinoma cells in mice.
[Mh] Termos MeSH primário: Inibidores Enzimáticos/química
Inibidores Enzimáticos/farmacologia
Glutaminase/antagonistas & inibidores
Tiazolidinedionas/química
Tiazolidinedionas/farmacologia
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/sangue
Antineoplásicos/química
Antineoplásicos/farmacologia
Antineoplásicos/uso terapêutico
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Desenho de Drogas
Inibidores Enzimáticos/sangue
Inibidores Enzimáticos/uso terapêutico
Glutaminase/metabolismo
Seres Humanos
Masculino
Camundongos
Camundongos Endogâmicos BALB C
Camundongos Nus
Modelos Moleculares
Pâncreas/efeitos dos fármacos
Pâncreas/metabolismo
Pâncreas/patologia
Neoplasias Pancreáticas/tratamento farmacológico
Neoplasias Pancreáticas/metabolismo
Neoplasias Pancreáticas/patologia
Ratos
Ratos Sprague-Dawley
Tiazolidinedionas/sangue
Tiazolidinedionas/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Enzyme Inhibitors); 0 (Thiazolidinediones); 0 (thiazolidine-2,4-dione); EC 3.5.1.2 (Glutaminase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170801
[Lr] Data última revisão:
170801
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170614
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00282


  9 / 1719 MEDLINE  
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[PMID]:28571744
[Au] Autor:Hur MW; Yoon JH; Kim MY; Ko H; Jeon BN
[Ad] Endereço:Department of Biochemistry and Molecular Biology, Yonsei University School of Medicine, 50-1 Yonsei-ro, SeoDaeMoon-ku, Seoul 03722, Republic of Korea.
[Ti] Título:Kr-POK (ZBTB7c) regulates cancer cell proliferation through glutamine metabolism.
[So] Source:Biochim Biophys Acta;1860(8):829-838, 2017 08.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo: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. Glutamine is critical for tumor cell proliferation. Glutaminase (GLS1), which is activated by p-STAT1, catalyzes the initial reaction in the pathway of glutaminolysis. Kr-POK interacts with PIAS1 to disrupt the interaction between PIAS1 and p-STAT1, and free p-STAT1 can activate GLS1 transcription through an interaction with p300. Kr-POK can be also sumoylated by PIAS1, facilitating Kr-POK degradation by the ubiquitin-mediated proteasomal pathway. Finally, we showed that repression of Kr-POK inhibited tumor growth in vivo in a xenograft model by repressing GLS1 expression. Taken together, our data reveal that Kr-POK activates GLS1 transcription and increases glutamine uptake to support rapid cancer cell proliferation.
[Mh] Termos MeSH primário: Proliferação Celular/genética
Glutamina/metabolismo
Proteínas/metabolismo
[Mh] Termos MeSH secundário: Animais
Morte Celular/genética
Linhagem Celular
Regulação Neoplásica da Expressão Gênica/genética
Glutaminase/metabolismo
Células HEK293
Seres Humanos
Masculino
Camundongos
Camundongos Endogâmicos BALB C
Camundongos Nus
Neoplasias/genética
Neoplasias/metabolismo
RNA Interferente Pequeno/genética
Fator de Transcrição STAT1/metabolismo
Fatores de Transcrição/metabolismo
Transcrição Genética/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Proteins); 0 (RNA, Small Interfering); 0 (STAT1 Transcription Factor); 0 (Transcription Factors); 0 (ZBTB7C protein, human); 0RH81L854J (Glutamine); EC 3.5.1.2 (Glutaminase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171026
[Lr] Data última revisão:
171026
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170603
[St] Status:MEDLINE


  10 / 1719 MEDLINE  
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[PMID]:28535436
[Au] Autor:Yan W; Li L; Li G; Zhao S
[Ad] Endereço:Institute of Agricultural Quality Standards & Testing Technology, Hubei Academy of Agricultural Sciences, Wuhan 430064, China.
[Ti] Título:Microcystin-LR induces changes in the GABA neurotransmitter system of zebrafish.
[So] Source:Aquat Toxicol;188:170-176, 2017 Jul.
[Is] ISSN:1879-1514
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:It has been reported that exposure to microcystins altered adult zebrafish swimming performance parameters, but the possible mechanisms of action remain unknown. Neuronal activity depends on the balance between the number of excitatory and inhibitory processes which are associated with neurotransmitters. In the present study, zebrafish embryos (5 d post-fertilization) were exposed to 0, 0.3, 3 and 30µg/L (microcystin-LR) MCLR for 90day until reaching sexual maturity. To investigate the effects of MCLR on the neurotransmitter system, mRNA levels involved in amino acid g-aminobutyric acid (GABA) and glutamate metabolic pathways were tested using quantitative real-time PCR. Significant increase of GABAA receptor, alpha 1 (gabra1), glutamate decarboxylase (gad1b), glutaminase (glsa) and reduction of mRNA expression of GABA transporter (gat1) at transcriptional level were observed in the brain. Meanwhile, western blotting showed that the protein levels of gabra1, gad1b were induced by MCLR, whereas the expression of gat1 was decreased. In addition, MCLR induced severe damage to cerebrum ultrastructure, showing edematous and collapsed myelinated nerve fibers, distention of endoplasmic reticulum and swelling mitochondria. Our results suggested that MCLR showed neurotoxicity in zebrafish which might attribute to the disorder of GABA neurotransmitter pathway.
[Mh] Termos MeSH primário: Embrião não Mamífero/efeitos dos fármacos
Microcistinas/toxicidade
Poluentes Químicos da Água/toxicidade
Peixe-Zebra/metabolismo
Ácido gama-Aminobutírico/metabolismo
[Mh] Termos MeSH secundário: Animais
Encéfalo/efeitos dos fármacos
Encéfalo/metabolismo
Encéfalo/patologia
Embrião não Mamífero/metabolismo
Proteínas da Membrana Plasmática de Transporte de GABA/genética
Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo
Glutamato Descarboxilase/genética
Glutamato Descarboxilase/metabolismo
Ácido Glutâmico/metabolismo
Glutaminase/genética
RNA Mensageiro/metabolismo
Reação em Cadeia da Polimerase em Tempo Real
Receptores de GABA-A/genética
Receptores de GABA-A/metabolismo
Peixe-Zebra/genética
Proteínas de Peixe-Zebra/genética
Proteínas de Peixe-Zebra/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (GABA Plasma Membrane Transport Proteins); 0 (Microcystins); 0 (RNA, Messenger); 0 (Receptors, GABA-A); 0 (Water Pollutants, Chemical); 0 (Zebrafish Proteins); 3KX376GY7L (Glutamic Acid); 56-12-2 (gamma-Aminobutyric Acid); EC 3.5.1.2 (Glutaminase); EC 4.1.1.15 (Glutamate Decarboxylase); EC 4.1.1.15 (glutamate decarboxylase 1); EQ8332842Y (cyanoginosin LR)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170524
[St] Status:MEDLINE



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