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Pesquisa : D12.776.157.530.200.374.600 [Categoria DeCS]
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[PMID]:29024663
[Au] Autor:Nasca C; Bigio B; Zelli D; de Angelis P; Lau T; Okamoto M; Soya H; Ni J; Brichta L; Greengard P; Neve RL; Lee FS; McEwen BS
[Ad] Endereço:Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065, USA. Electronic address: cnasca@rockefeller.edu.
[Ti] Título:Role of the Astroglial Glutamate Exchanger xCT in Ventral Hippocampus in Resilience to Stress.
[So] Source:Neuron;96(2):402-413.e5, 2017 Oct 11.
[Is] ISSN:1097-4199
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We demonstrate that stress differentially regulates glutamate homeostasis in the dorsal and ventral hippocampus and identify a role for the astroglial xCT in ventral dentate gyrus (vDG) in stress and antidepressant responses. We provide an RNA-seq roadmap for the stress-sensitive vDG. The transcription factor REST binds to xCT promoter in co-occupancy with the epigenetic marker H3K27ac to regulate expression of xCT, which is also reduced in a genetic mouse model of inherent susceptibility to depressive-like behavior. Pharmacologically, modulating histone acetylation with acetyl-L-carnitine (LAC) or acetyl-N-cysteine (NAC) rapidly increases xCT and activates a network with mGlu2 receptors to prime an enhanced glutamate homeostasis that promotes both pro-resilient and antidepressant-like responses. Pharmacological xCT blockage counteracts NAC prophylactic effects. GFAP -Cre-dependent overexpression of xCT in vDG mimics pharmacological actions in promoting resilience. This work establishes a mechanism by which vDG protection leads to stress resilience and antidepressant responses via epigenetic programming of an xCT-mGlu2 network.
[Mh] Termos MeSH primário: Sistema y+ de Transporte de Aminoácidos/fisiologia
Astrócitos/fisiologia
Ácido Glutâmico/metabolismo
Hipocampo/fisiologia
Estresse Psicológico/metabolismo
[Mh] Termos MeSH secundário: Animais
Depressão/genética
Depressão/metabolismo
Depressão/psicologia
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Distribuição Aleatória
Receptores de Glutamato Metabotrópico/genética
Receptores de Glutamato Metabotrópico/metabolismo
Estresse Psicológico/genética
Estresse Psicológico/psicologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acid Transport System y+); 0 (Receptors, Metabotropic Glutamate); 0 (Slc7a11 protein, mouse); 0 (metabotropic glutamate receptor 2); 3KX376GY7L (Glutamic Acid)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171020
[Lr] Data última revisão:
171020
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171013
[St] Status:MEDLINE


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[PMID]:28985506
[Au] Autor:Chen D; Tavana O; Chu B; Erber L; Chen Y; Baer R; Gu W
[Ad] Endereço:Institute for Cancer Genetics, Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, 1130 St. Nicholas Avenue, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, 1130 St. Nicholas
[Ti] Título:NRF2 Is a Major Target of ARF in p53-Independent Tumor Suppression.
[So] Source:Mol Cell;68(1):224-232.e4, 2017 Oct 05.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Although ARF can suppress tumor growth by activating p53 function, the mechanisms by which it suppresses tumor growth independently of p53 are not well understood. Here, we identified ARF as a key regulator of nuclear factor E2-related factor 2 (NRF2) through complex purification. ARF inhibits the ability of NRF2 to transcriptionally activate its target genes, including SLC7A11, a component of the cystine/glutamate antiporter that regulates reactive oxygen species (ROS)-induced ferroptosis. As a consequence, ARF expression sensitizes cells to ferroptosis in a p53-independent manner while ARF depletion induces NRF2 activation and promotes cancer cell survival in response to oxidative stress. Moreover, the ability of ARF to induce p53-independent tumor growth suppression in mouse xenograft models is significantly abrogated upon NRF2 overexpression. These results demonstrate that NRF2 is a major target of p53-independent tumor suppression by ARF and also suggest that the ARF-NRF2 interaction acts as a new checkpoint for oxidative stress responses.
[Mh] Termos MeSH primário: Sistema y+ de Transporte de Aminoácidos/genética
Neoplasias Ósseas/genética
Inibidor de Quinase Dependente de Ciclina p18/genética
Regulação Neoplásica da Expressão Gênica
Fator 2 Relacionado a NF-E2/genética
[Mh] Termos MeSH secundário: Sistema y+ de Transporte de Aminoácidos/metabolismo
Animais
Neoplasias Ósseas/metabolismo
Neoplasias Ósseas/patologia
Linhagem Celular Tumoral
Inibidor de Quinase Dependente de Ciclina p18/metabolismo
Células Epiteliais/metabolismo
Células Epiteliais/patologia
Fibroblastos/citologia
Fibroblastos/metabolismo
Células HEK293
Xenoenxertos
Seres Humanos
Camundongos
Camundongos Nus
Fator 2 Relacionado a NF-E2/metabolismo
Osteoblastos/metabolismo
Osteoblastos/patologia
Estresse Oxidativo
Espécies Reativas de Oxigênio/metabolismo
Transdução de Sinais
Proteína Supressora de Tumor p53/genética
Proteína Supressora de Tumor p53/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acid Transport System y+); 0 (CDKN2A protein, human); 0 (Cyclin-Dependent Kinase Inhibitor p18); 0 (NF-E2-Related Factor 2); 0 (NFE2L2 protein, human); 0 (Reactive Oxygen Species); 0 (SLC7A11 protein, human); 0 (Tumor Suppressor Protein p53)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171115
[Lr] Data última revisão:
171115
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171007
[St] Status:MEDLINE


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[PMID]:28648777
[Au] Autor:Gu Y; Albuquerque CP; Braas D; Zhang W; Villa GR; Bi J; Ikegami S; Masui K; Gini B; Yang H; Gahman TC; Shiau AK; Cloughesy TF; Christofk HR; Zhou H; Guan KL; Mischel PS
[Ad] Endereço:Department of Molecular and Medical Pharmacology, David Geffen UCLA School of Medicine, Los Angeles, CA 90095, USA; Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
[Ti] Título:mTORC2 Regulates Amino Acid Metabolism in Cancer by Phosphorylation of the Cystine-Glutamate Antiporter xCT.
[So] Source:Mol Cell;67(1):128-138.e7, 2017 Jul 06.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mutations in cancer reprogram amino acid metabolism to drive tumor growth, but the molecular mechanisms are not well understood. Using an unbiased proteomic screen, we identified mTORC2 as a critical regulator of amino acid metabolism in cancer via phosphorylation of the cystine-glutamate antiporter xCT. mTORC2 phosphorylates serine 26 at the cytosolic N terminus of xCT, inhibiting its activity. Genetic inhibition of mTORC2, or pharmacologic inhibition of the mammalian target of rapamycin (mTOR) kinase, promotes glutamate secretion, cystine uptake, and incorporation into glutathione, linking growth factor receptor signaling with amino acid uptake and utilization. These results identify an unanticipated mechanism regulating amino acid metabolism in cancer, enabling tumor cells to adapt to changing environmental conditions.
[Mh] Termos MeSH primário: Sistema y+ de Transporte de Aminoácidos/metabolismo
Neoplasias Encefálicas/enzimologia
Cisteína/metabolismo
Glioblastoma/enzimologia
Glutamina/metabolismo
Complexos Multiproteicos/metabolismo
Serina-Treonina Quinases TOR/metabolismo
[Mh] Termos MeSH secundário: Células A549
Sistema y+ de Transporte de Aminoácidos/genética
Neoplasias Encefálicas/genética
Neoplasias Encefálicas/patologia
Glioblastoma/genética
Glioblastoma/patologia
Glutationa/biossíntese
Células HEK293
Seres Humanos
Alvo Mecanístico do Complexo 1 de Rapamicina
Complexos Multiproteicos/genética
Mutação
Fosforilação
Ligação Proteica
Proteômica/métodos
Interferência de RNA
Serina
Serina-Treonina Quinases TOR/genética
Espectrometria de Massas em Tandem
Fatores de Tempo
Transfecção
Microambiente Tumoral
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acid Transport System y+); 0 (Multiprotein Complexes); 0 (SLC7A11 protein, human); 0RH81L854J (Glutamine); 452VLY9402 (Serine); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1); GAN16C9B8O (Glutathione); K848JZ4886 (Cysteine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170627
[St] Status:MEDLINE


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[PMID]:28630042
[Au] Autor:Koppula P; Zhang Y; Shi J; Li W; Gan B
[Ad] Endereço:From the Departments of Experimental Radiation Oncology and.
[Ti] Título:The glutamate/cystine antiporter SLC7A11/xCT enhances cancer cell dependency on glucose by exporting glutamate.
[So] Source:J Biol Chem;292(34):14240-14249, 2017 Aug 25.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cancer cells with specific genetic alterations may be highly dependent on certain nutrients for survival, which can inform therapeutic strategies to target these cancer-specific metabolic vulnerabilities. The glutamate/cystine antiporter solute carrier family 7 member 11 (SLC7A11, also called xCT) is overexpressed in several cancers. Contrasting the established pro-survival roles of SLC7A11 under other stress conditions, here we report the unexpected finding that overexpression enhances cancer cell dependence on glucose and renders cancer cells more sensitive to glucose starvation-induced cell death and, conversely, that deficiency by either knockdown or pharmacological inhibition promotes cancer cell survival upon glucose starvation. We further show that glucose starvation induces expression through ATF4 and NRF2 transcription factors and, correspondingly, that or deficiency also renders cancer cells more resistant to glucose starvation. Finally, we show that overexpression decreases whereas deficiency increases intracellular glutamate levels because of SLC7A11-mediated glutamate export and that supplementation of α-ketoglutarate, a key downstream metabolite of glutamate, fully restores survival in -overexpressing cells under glucose starvation. Together, our results support the notion that both glucose and glutamate have important roles in maintaining cancer cell survival and uncover a previously unappreciated role of SLC7A11 to promote cancer cell dependence on glucose. Our study therefore informs therapeutic strategies to target the metabolic vulnerability in tumors with high expression.
[Mh] Termos MeSH primário: Sistema y+ de Transporte de Aminoácidos/metabolismo
Metabolismo Energético
Regulação Neoplásica da Expressão Gênica
Ácido Glutâmico/metabolismo
Proteínas de Neoplasias/metabolismo
Neoplasias/metabolismo
[Mh] Termos MeSH secundário: Absorção Fisiológica
Sistema y+ de Transporte de Aminoácidos/antagonistas & inibidores
Sistema y+ de Transporte de Aminoácidos/genética
Animais
Sistemas CRISPR-Cas
Linhagem Celular Tumoral
Sobrevivência Celular
Células Cultivadas
Embrião de Mamíferos/citologia
Glucose/metabolismo
Células HEK293
Seres Humanos
Ácidos Cetoglutáricos/metabolismo
Camundongos
Proteínas de Neoplasias/antagonistas & inibidores
Proteínas de Neoplasias/genética
Neoplasias/enzimologia
Neoplasias/patologia
Proteínas Recombinantes/metabolismo
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acid Transport System y+); 0 (Ketoglutaric Acids); 0 (Neoplasm Proteins); 0 (Recombinant Proteins); 0 (SLC7A11 protein, human); 0 (Slc7a11 protein, mouse); 3KX376GY7L (Glutamic Acid); 8ID597Z82X (alpha-ketoglutaric acid); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170621
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.798405


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[PMID]:28624579
[Au] Autor:Nano J; Ghanbari M; Wang W; de Vries PS; Dhana K; Muka T; Uitterlinden AG; van Meurs JBJ; Hofman A; Franco OH; Pan Q; Murad SD; Dehghan A; BIOS consortium
[Ad] Endereço:Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
[Ti] Título:Epigenome-Wide Association Study Identifies Methylation Sites Associated With Liver Enzymes and Hepatic Steatosis.
[So] Source:Gastroenterology;153(4):1096-1106.e2, 2017 Oct.
[Is] ISSN:1528-0012
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND & AIMS: Epigenetic mechanisms might be involved in the regulation of liver enzyme level. We aimed to identify CpG sites at which DNA methylation levels are associated with blood levels of liver enzymes and hepatic steatosis. METHODS: We conducted an epigenome-wide association study in whole blood for liver enzyme levels, including gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST), among a discovery set of 731 participants of the Rotterdam Study and sought replication in a non-overlapping sample of 719 individuals. Significant DNA methylation changes were further analyzed to evaluate their relation with hepatic steatosis. Expression levels of the top identified gene were measured in 9 human liver cell lines and compared with expression profiles of its potential targets associated with lipid traits. The candidate gene was subsequently knocked down in human hepatoma cells using lentiviral vectors expressing small hairpin RNAs. RESULTS: Eight probes annotated to SLC7A11, SLC1A5, SLC43A1, PHGDH, PSORS1C1, SREBF1, ANKS3 were associated with GGT and 1 probe annotated to SLC7A11 was associated with ALT after Bonferroni correction (1.0 × 10 ). No probe was identified for AST levels. Four probes for GGT levels including cg06690548 (SLC7A11), cg11376147 (SLC43A1), cg22304262 (SLC1A5), and cg14476101 (PHGDH), and 1 for ALT cg06690548 (SLC7A11) were replicated. DNA methylation at SLC7A11 was associated with reduced risk of hepatic steatosis in participants (odds ratio, 0.69; 95% CI= 0.55-0.93; P value: 2.7 × 10 ). In functional experiments, SLC7A11 was highly expressed in human liver cells; its expression is positively correlated with expression of a panel of lipid-associated genes, indicating a role of SLC7A11 in lipid metabolism. CONCLUSIONS: Our results provide new insights into epigenetic mechanisms associated with markers of liver function and hepatic steatosis, laying the groundwork for future diagnostic and therapeutic applications.
[Mh] Termos MeSH primário: Alanina Transaminase/sangue
Sistema y+ de Transporte de Aminoácidos/genética
Aspartato Aminotransferases/sangue
Metilação de DNA
Epigênese Genética
Fígado Gorduroso/genética
Metabolismo dos Lipídeos/genética
gama-Glutamiltransferase/sangue
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Sistema ASC de Transporte de Aminoácidos/genética
Sistema ASC de Transporte de Aminoácidos/metabolismo
Sistema y+ de Transporte de Aminoácidos/metabolismo
Sistema y+L de Transporte de Aminoácidos/genética
Sistema y+L de Transporte de Aminoácidos/metabolismo
Biomarcadores/sangue
Linhagem Celular Tumoral
Ilhas de CpG
Fígado Gorduroso/sangue
Fígado Gorduroso/enzimologia
Fígado Gorduroso/prevenção & controle
Feminino
Predisposição Genética para Doença
Estudo de Associação Genômica Ampla
Seres Humanos
Masculino
Análise da Randomização Mendeliana
Meia-Idade
Antígenos de Histocompatibilidade Menor/genética
Antígenos de Histocompatibilidade Menor/metabolismo
Proteínas de Neoplasias/genética
Proteínas de Neoplasias/metabolismo
Países Baixos
Razão de Chances
Fenótipo
Fosfoglicerato Desidrogenase/genética
Fosfoglicerato Desidrogenase/metabolismo
Fatores de Proteção
Interferência de RNA
Medição de Risco
Fatores de Risco
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE; VIDEO-AUDIO MEDIA
[Nm] Nome de substância:
0 (Amino Acid Transport System ASC); 0 (Amino Acid Transport System y+); 0 (Amino Acid Transport System y+L); 0 (Biomarkers); 0 (Minor Histocompatibility Antigens); 0 (Neoplasm Proteins); 0 (SLC1A5 protein, human); 0 (SLC43A1 protein, human); 0 (SLC7A11 protein, human); EC 1.1.1.95 (Phosphoglycerate Dehydrogenase); EC 2.3.2.2 (gamma-Glutamyltransferase); EC 2.3.2.2 (gamma-glutamyltransferase, human); EC 2.6.1.1 (Aspartate Aminotransferases); EC 2.6.1.2 (Alanine Transaminase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170619
[St] Status:MEDLINE


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[PMID]:28553953
[Au] Autor:Chen D; Fan Z; Rauh M; Buchfelder M; Eyupoglu IY; Savaskan N
[Ad] Endereço:Translational Cell Biology &Neurooncology Laboratory, Universitätsklinikum Erlangen (UKER), Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
[Ti] Título:ATF4 promotes angiogenesis and neuronal cell death and confers ferroptosis in a xCT-dependent manner.
[So] Source:Oncogene;36(40):5593-5608, 2017 Oct 05.
[Is] ISSN:1476-5594
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Activating transcription factor 4 (ATF4) is a critical mediator of metabolic and oxidative homeostasis and cell survival. ATF4 is elevated in response to diverse microenvironmental stresses, including starvation, ER stress damages and exposure to toxic factors. Here we show that ATF4 expression fosters the malignancy of primary brain tumors (WHO grade III and IV gliomas) and increases proliferation and tumor angiogenesis. Hence, ATF4 expression promotes cell migration and anchorage-independent cell growth, whereas siRNA-mediated knockdown of ATF4 attenuates these features of malignancy in human gliomas. Further experiments revealed that ATF4-dependent tumor promoting effects are mediated by transcriptional targeting the glutamate antiporter xCT/SCL7A11 (also known as system Xc ). Thus, xCT is elevated as a consequence of ATF4 activation. We further found evidence that ATF4-induced proliferation can be attenuated by pharmacological or genetic xCT inhibition and ferroptosis inducers such as sorafenib, erastin and GPx4 inhibitor RSL3. Further, fostered xCT expression promotes cell survival and growth in ATF4 knockdown cells. Moreover, increased xCT levels ameliorate sorafenib and erastin-induced ferroptosis. Conversely, ATF4 knockdown renders cells susceptible for erastin, sorafenib and RSL3-induced ferroptosis. We further identified that ATF4 promotes tumor-mediated neuronal cell death which can be alleviated by xCT inhibition. Moreover, elevated ATF4 expression in gliomas promotes tumor angiogenesis. Noteworthy, ATF4-induced angiogenesis could be diminished by ferroptosis inducers erastin and by GPx4 inhibitor RSL3. Our data provide proof-of-principle evidence that ATF4 fosters proliferation and induces a toxic microenvironmental niche. Furthermore, ATF4 increases tumor angiogenesis and shapes the vascular architecture in a xCT-dependent manner. Thus, inhibition of ATF4 is a valid target for diminishing tumor growth and vasculature via sensitizing tumor cells for ferroptosis.
[Mh] Termos MeSH primário: Fator 4 Ativador da Transcrição/metabolismo
Sistema y+ de Transporte de Aminoácidos/metabolismo
Neoplasias Encefálicas/irrigação sanguínea
Morte Celular
Glioma/irrigação sanguínea
Neovascularização Patológica
[Mh] Termos MeSH secundário: Fator 4 Ativador da Transcrição/genética
Sistema y+ de Transporte de Aminoácidos/genética
Neoplasias Encefálicas/metabolismo
Linhagem Celular Tumoral
Proliferação Celular
Regulação Neoplásica da Expressão Gênica
Glioma/metabolismo
Ácido Glutâmico/secreção
Seres Humanos
Ferro/metabolismo
Neurônios/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ATF4 protein, human); 0 (Amino Acid Transport System y+); 0 (SLC7A11 protein, human); 145891-90-3 (Activating Transcription Factor 4); 3KX376GY7L (Glutamic Acid); E1UOL152H7 (Iron)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170530
[St] Status:MEDLINE
[do] DOI:10.1038/onc.2017.146


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[PMID]:28273808
[Au] Autor:Russo A; Saide A; Smaldone S; Faraonio R; Russo G
[Ad] Endereço:Department of Pharmacy, University of Naples "Federico II", Via Domenico Montesano 49, 80131 Naples, Italy. annapina.russo@unina.it.
[Ti] Título:Role of uL3 in Multidrug Resistance in p53-Mutated Lung Cancer Cells.
[So] Source:Int J Mol Sci;18(3), 2017 Mar 03.
[Is] ISSN:1422-0067
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Cancer is one of the most common causes of death among adults. Chemotherapy is crucial in determining patient survival and quality of life. However, the development of multidrug resistance (MDR) continues to pose a significant challenge in the management of cancer. In this study, we analyzed the role of human ribosomal protein uL3 (formerly rpL3) in multidrug resistance. Our studies revealed that uL3 is a key determinant of multidrug resistance in -mutated lung cancer cells by controlling the cell redox status. We established and characterized a multidrug resistant Calu-6 cell line. We found that uL3 down-regulation correlates positively with multidrug resistance. Restoration of the uL3 protein level re-sensitized the resistant cells to the drug by regulating the reactive oxygen species (ROS) levels, glutathione content, glutamate release, and cystine uptake. Chromatin immunoprecipitation experiments and luciferase assays demonstrated that uL3 coordinated the expression of stress-response genes acting as transcriptional repressors of solute carrier family 7 member 11 ( ) and glutathione -transferase α1 ( ), independently of Nuclear factor erythroid 2-related factor 2 (Nrf2). Altogether our results describe a new function of uL3 as a regulator of oxidative stress response genes and advance our understanding of the molecular mechanisms underlying multidrug resistance in cancers.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Resistência a Múltiplos Medicamentos
Resistência a Medicamentos Antineoplásicos
Neoplasias Pulmonares/genética
Neoplasias Pulmonares/metabolismo
Mutação
Proteínas Ribossômicas/metabolismo
Proteína Supressora de Tumor p53/genética
[Mh] Termos MeSH secundário: Sistema y+ de Transporte de Aminoácidos/genética
Sistema y+ de Transporte de Aminoácidos/metabolismo
Linhagem Celular Tumoral
Células Cultivadas
Resistência a Múltiplos Medicamentos/genética
Resistência a Medicamentos Antineoplásicos/genética
Regulação Neoplásica da Expressão Gênica
Glutationa Transferase/genética
Glutationa Transferase/metabolismo
Seres Humanos
Isoenzimas/genética
Isoenzimas/metabolismo
Modelos Biológicos
Estresse Oxidativo
Espécies Reativas de Oxigênio/metabolismo
Proteínas Repressoras/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acid Transport System y+); 0 (Antineoplastic Agents); 0 (Isoenzymes); 0 (Reactive Oxygen Species); 0 (Repressor Proteins); 0 (Ribosomal Proteins); 0 (SLC7A11 protein, human); 0 (Tumor Suppressor Protein p53); 0 (ribosomal protein L3); EC 2.5.1.18 (Glutathione Transferase); EC 2.5.1.18 (glutathione S-transferase alpha)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170420
[Lr] Data última revisão:
170420
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170310
[St] Status:MEDLINE


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[PMID]:28167131
[Au] Autor:Martin C; Patel M; Melendez-Ferro M; Sims B
[Ad] Endereço:Department of Surgery/Division of Pediatric Surgery and Center of Glial Biology in Medicine at the University of Alabama School of Medicine, Birmingham, AL 35294, USA.
[Ti] Título:Erythropoietin-induced cytoprotection in intestinal epithelial cells is linked to system Xc .
[So] Source:Exp Cell Res;352(2):202-206, 2017 Mar 15.
[Is] ISSN:1090-2422
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Necrotizing enterocolitis is a common but serious complication among premature babies. Currently, there are limited treatment options. These include intensive supportive care and surgical intervention. In this study, we hypothesize that erythropoietin (Epo) could be protective against cell necrosis by increasing the levels of glutathione. This can be regulated by increasing the activity of system xC . This was demonstrated using intestinal epithelial cells (IEC-6) as a model system. S4-CPG and sulfasalazine pharmacologically inhibit xCT, which induced cell death. Our data showed a dose dependent decrease in cell viability when treated with both inhibitors. In addition, the IEC-6 cells displayed a dose dependent increase when treated with Epo. In conclusion, Epo can be protective against cell death and ultimately be considered as a treatment option for intestinal epithelial cell death.
[Mh] Termos MeSH primário: Sistema y+ de Transporte de Aminoácidos/metabolismo
Enterocolite Necrosante/metabolismo
Eritropoetina/farmacologia
Mucosa Intestinal/metabolismo
[Mh] Termos MeSH secundário: Sistema y+ de Transporte de Aminoácidos/antagonistas & inibidores
Sistema y+ de Transporte de Aminoácidos/genética
Animais
Linhagem Celular
Sobrevivência Celular/efeitos dos fármacos
Enterocolite Necrosante/patologia
Glutationa/metabolismo
Seres Humanos
Lactente
Mucosa Intestinal/efeitos dos fármacos
Mucosa Intestinal/patologia
Ratos
Sulfassalazina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acid Transport System y+); 0 (SLC7A11 protein, human); 11096-26-7 (Erythropoietin); 3XC8GUZ6CB (Sulfasalazine); GAN16C9B8O (Glutathione)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170526
[Lr] Data última revisão:
170526
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170208
[St] Status:MEDLINE


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[PMID]:28081640
[Au] Autor:Kang ES; Lee J; Homma T; Kurahashi T; Kobayashi S; Nabeshima A; Yamada S; Seo HG; Miyata S; Sato H; Fujii J
[Ad] Endereço:a Department of Biochemistry and Molecular Biology , Graduate School of Medical Science, Yamagata University , Yamagata , Japan.
[Ti] Título:xCT deficiency aggravates acetaminophen-induced hepatotoxicity under inhibition of the transsulfuration pathway.
[So] Source:Free Radic Res;51(1):80-90, 2017 Jan.
[Is] ISSN:1029-2470
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Cystine, an oxidized form of cysteine (Cys), is imported into cells via the protein xCT, which is also associated with the export of glutamate as the counter amino acid. In the current study, we attempted to rationalize roles of xCT in the livers of male mice. While xCT was not expressed in the livers of ordinary mice, it was induced under conditions of glutathione depletion, caused by the administration of acetaminophen (AAP). To differentiate the role between xCT and the transsulfuration pathway on the supply of Cys, we employed an inhibitor of the enzyme cystathionine γ-lyase, propargylglycine (PPG). This inhibitor caused a marked aggravation in AAP-induced hepatic damage and the mortality of the xCT mice was increased to a greater extent than that for the xCT mice. While a PPG pretreatment had no effect on liver condition or Cys levels, the administration of AAP to the PPG-pretreated mice reduced the levels of Cys as well as glutathione to very low levels in both the xCT and xCT mice. These findings indicate that the transsulfuration pathway plays a major role in replenishing Cys when glutathione levels are low. Moreover, an ascorbic acid insufficiency, induced by Akr1a ablation, further aggravated the AAP-induced liver damage in the case of the xCT deficiency, indicating that glutathione and ascorbic acid function cooperatively in protecting the liver. In conclusion, while the transsulfuration pathway plays a primary role in supplying Cys to the redox system in the liver, xCT is induced in cases of emergencies, by compensating for Cys supply systems.
[Mh] Termos MeSH primário: Acetaminofen/toxicidade
Sistema y+ de Transporte de Aminoácidos/genética
Doença Hepática Induzida por Substâncias e Drogas/metabolismo
[Mh] Termos MeSH secundário: Sistema y+ de Transporte de Aminoácidos/metabolismo
Animais
Doença Hepática Induzida por Substâncias e Drogas/genética
Cisteína/metabolismo
Glutationa/metabolismo
Masculino
Camundongos Endogâmicos C57BL
Camundongos Knockout
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acid Transport System y+); 0 (Slc7a11 protein, mouse); 362O9ITL9D (Acetaminophen); GAN16C9B8O (Glutathione); K848JZ4886 (Cysteine)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170307
[Lr] Data última revisão:
170307
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170114
[St] Status:MEDLINE
[do] DOI:10.1080/10715762.2017.1282157


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[PMID]:28070112
[Au] Autor:Tobe T; Ueda K; Aoki A; Okamoto Y; Kojima N; Jinno H
[Ad] Endereço:Faculty of Pharmacy, Meijo University.
[Ti] Título:Selenium uptake through cystine transporter mediated by glutathione conjugation.
[So] Source:J Toxicol Sci;42(1):85-91, 2017.
[Is] ISSN:1880-3989
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:Selenium (Se) is an essential trace element and is regarded as a protective agent against cancer. In particular, antioxidant effects of selenoenzymes contribute to cancer prevention. Se can also produce reactive oxygen species and, thereby, exert cancer-selective cytotoxicity. Selenodiglutathione (SDG) is a primary Se metabolite conjugated to two glutathione (GSH) moieties. SDG increases intracellular Se accumulation and is more toxic than selenous acid (H SeO ), but the mechanisms for importing Se compounds into cells are not fully understood. Here, we propose a novel mechanism for importing Se, in the form of SDG. Cellular intake of Se compounds was assessed based on Se accumulation, as detected by ICP-MS. SDG incorporation was decreased in the presence of thiols (GSH, cysteine or their oxidized forms, GSSG and cystine), whereas H SeO uptake was increased by addition of GSH or cysteine. Cellular SDG uptake was decreased by pretreatment with specific inhibitors against gamma-glutamyl transpeptidase (GGT) or the cystine/glutamate antiporter (system x ). Furthermore, siRNA against xCT, which is the light chain component of system x , significantly decreased SDG incorporation. These data suggest an involvement of SDG in Se incorporation, with SDG processed at the cell surface by GGT, leading to formation of selenodicysteine which, in turn, is likely to be imported via xCT. Because GGT and xCT are highly expressed in cancer cells, these mechanisms mediated by the cystine transporter might underlie the cancer-selective toxicity of Se. In addition, the system described in our study appears to represent a physiological transport mechanism for the essential element Se.
[Mh] Termos MeSH primário: Sistema y+ de Transporte de Aminoácidos/genética
Glutationa/análogos & derivados
Compostos Organosselênicos/farmacologia
Ácido Selenioso/farmacologia
[Mh] Termos MeSH secundário: Glutationa/farmacologia
Seres Humanos
Células MCF-7
RNA Interferente Pequeno/genética
Selênio/metabolismo
gama-Glutamiltransferase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acid Transport System y+); 0 (Organoselenium Compounds); 0 (RNA, Small Interfering); 0 (SLC7A11 protein, human); 33944-90-0 (selenodiglutathione); EC 2.3.2.2 (gamma-Glutamyltransferase); F6A27P4Q4R (Selenious Acid); GAN16C9B8O (Glutathione); H6241UJ22B (Selenium)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170523
[Lr] Data última revisão:
170523
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170111
[St] Status:MEDLINE
[do] DOI:10.2131/jts.42.85



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