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[PMID]:27770401
[Au] Autor:Schulte ML; Hight MR; Ayers GD; Liu Q; Shyr Y; Washington MK; Manning HC
[Ad] Endereço:Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
[Ti] Título:Non-Invasive Glutamine PET Reflects Pharmacological Inhibition of BRAF In Vivo.
[So] Source:Mol Imaging Biol;19(3):421-428, 2017 06.
[Is] ISSN:1860-2002
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:PURPOSE: This study aimed to study whether cancer cells possess distinguishing metabolic features compared with surrounding normal cells, such as increased glutamine uptake. Given this, quantitative measures of glutamine uptake may reflect critical processes in oncology. Approximately, 10 % of patients with colorectal cancer (CRC) express BRAF , which may be actionable with selective BRAF inhibitors or in combination with inhibitors of complementary signaling axes. Non-invasive and quantitative predictive measures of response to these targeted therapies remain poorly developed in this setting. The primary objective of this study was to explore 4-[ F]fluoroglutamine (4-[ F]F-GLN) positron emission tomography (PET) to predict response to BRAF -targeted therapy in preclinical models of colon cancer. PROCEDURES: Tumor microarrays from patients with primary human colon cancers (n = 115) and CRC liver metastases (n = 111) were used to evaluate the prevalence of ASCT2, the primary glutamine transporter in oncology, by immunohistochemistry. Subsequently, 4-[ F]F-GLN PET was evaluated in mouse models of human BRAF -expressing and BRAF wild-type CRC. RESULTS: Approximately 70 % of primary colon cancers and 53 % of metastases exhibited positive ASCT2 immunoreactivity, suggesting that [ F]4-F-GLN PET could be applicable to a majority of patients with colon cancer. ASCT2 expression was not associated selectively with the expression of mutant BRAF. Decreased 4-[ F]F-GLN predicted pharmacological response to single-agent BRAF and combination BRAF and PI3K/mTOR inhibition in BRAF -mutant Colo-205 tumors. In contrast, a similar decrease was not observed in BRAF wild-type HCT-116 tumors, a setting where BRAF -targeted therapies are ineffective. CONCLUSIONS: 4-[ F]F-GLN PET selectively reflected pharmacodynamic response to BRAF inhibition when compared with 2-deoxy-2[ F]fluoro-D-glucose PET, which was decreased non-specifically for all treated cohorts, regardless of downstream pathway inhibition. These findings illustrate the utility of non-invasive PET imaging measures of glutamine uptake to selectively predict response to BRAF-targeted therapy in colon cancer and may suggest further opportunities to inform colon cancer clinical trials using targeted therapies against MAPK activation.
[Mh] Termos MeSH primário: Glutamina/química
Mutação/genética
Tomografia por Emissão de Pósitrons
Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores
Proteínas Proto-Oncogênicas B-raf/genética
[Mh] Termos MeSH secundário: Sistema ASC de Transporte de Aminoácidos/metabolismo
Animais
Linhagem Celular Tumoral
Neoplasias do Colo/tratamento farmacológico
Neoplasias do Colo/metabolismo
Neoplasias do Colo/patologia
Feminino
Seres Humanos
Neoplasias Hepáticas/secundário
Camundongos Nus
Antígenos de Histocompatibilidade Menor/metabolismo
Inibidores de Proteínas Quinases/farmacologia
Inibidores de Proteínas Quinases/uso terapêutico
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Amino Acid Transport System ASC); 0 (Minor Histocompatibility Antigens); 0 (Protein Kinase Inhibitors); 0 (SLC1A5 protein, human); 0RH81L854J (Glutamine); EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161023
[St] Status:MEDLINE
[do] DOI:10.1007/s11307-016-1008-z


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[PMID]:28823958
[Au] Autor:Tao X; Lu Y; Qiu S; Wang Y; Qin J; Fan Z
[Ad] Endereço:Department of Oral Medicine, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong 510055, China; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
[Ti] Título:AP1G1 is involved in cetuximab-mediated downregulation of ASCT2-EGFR complex and sensitization of human head and neck squamous cell carcinoma cells to ROS-induced apoptosis.
[So] Source:Cancer Lett;408:33-42, 2017 Nov 01.
[Is] ISSN:1872-7980
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:In this study, we expanded our recent work showing that ASCT2, a Na -dependent neutral amino acid transporter that plays a major role in glutamine uptake in cancer cells, is physically associated with EGFR in human head and neck squamous cell carcinoma cells and in several other types of cancer cells. We found in our current study that ASCT2 can be downregulated by cetuximab, an approved anti-EGFR therapeutic antibody, via cetuximab-induced EGFR endocytosis independently of cetuximab-mediated inhibition of EGFR tyrosine kinase. We further found that ASCT2-EGFR association involves the adaptor-related protein complex 1 gamma 1 subunit (AP1G1), a subunit of clathrin-associated adaptor protein complex 1, which plays a role in membrane protein sorting in endosomes after receptor-mediated endocytosis. We found that AP1G1 is physically associated with both ASCT2 and EGFR and, together with those molecules, forms a heterotrimeric molecular complex. Knockdown of AP1G1 lowered the level of ASCT2-EGFR association, inhibited cetuximab-mediated internalization of ASCT2-EGFR complex, and decreased intracellular glutamine uptake and glutathione biosynthesis. These findings suggest a new therapeutic strategy to overcome cetuximab resistance in cancer cells through combination of cetuximab, which co-targets ASCT2 along with EGFR, with an ROS-inducing agent.
[Mh] Termos MeSH primário: Subunidades gama do Complexo de Proteínas Adaptadoras/metabolismo
Sistema ASC de Transporte de Aminoácidos/antagonistas & inibidores
Apoptose/efeitos dos fármacos
Cetuximab/farmacologia
Resistência a Medicamentos Antineoplásicos
Neoplasias de Cabeça e Pescoço/patologia
Espécies Reativas de Oxigênio/metabolismo
Receptor do Fator de Crescimento Epidérmico/antagonistas & inibidores
[Mh] Termos MeSH secundário: Subunidades gama do Complexo de Proteínas Adaptadoras/genética
Sistema ASC de Transporte de Aminoácidos/genética
Sistema ASC de Transporte de Aminoácidos/metabolismo
Antineoplásicos/farmacologia
Carcinoma de Células Escamosas/tratamento farmacológico
Carcinoma de Células Escamosas/metabolismo
Carcinoma de Células Escamosas/patologia
Proliferação Celular/efeitos dos fármacos
Neoplasias de Cabeça e Pescoço/tratamento farmacológico
Neoplasias de Cabeça e Pescoço/metabolismo
Seres Humanos
Antígenos de Histocompatibilidade Menor/genética
Antígenos de Histocompatibilidade Menor/metabolismo
Receptor do Fator de Crescimento Epidérmico/genética
Receptor do Fator de Crescimento Epidérmico/metabolismo
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Protein Complex gamma Subunits); 0 (Amino Acid Transport System ASC); 0 (Antineoplastic Agents); 0 (Minor Histocompatibility Antigens); 0 (Reactive Oxygen Species); 0 (SLC1A5 protein, human); EC 2.7.10.1 (EGFR protein, human); EC 2.7.10.1 (Receptor, Epidermal Growth Factor); PQX0D8J21J (Cetuximab)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170822
[St] Status:MEDLINE


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[PMID]:28784848
[Au] Autor:Jensen H; Potempa M; Gotthardt D; Lanier LL
[Ad] Endereço:Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143; and.
[Ti] Título:Cutting Edge: IL-2-Induced Expression of the Amino Acid Transporters SLC1A5 and CD98 Is a Prerequisite for NKG2D-Mediated Activation of Human NK Cells.
[So] Source:J Immunol;199(6):1967-1972, 2017 Sep 15.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Priming of human NK cells with IL-2 is necessary to render them functionally competent upon NKG2D engagement. We examined the underlying mechanisms that control NKG2D responsiveness in NK cells and found that IL-2 upregulates expression of the amino acid transporters SLC1A5 and CD98. Using specific inhibitors to block SLC1A5 and CD98 function, we found that production of IFN-γ and degranulation by CD56 and CD56 NK cells following NKG2D stimulation were dependent on both transporters. IL-2 priming increased the activity of mTORC1, and inhibition of mTORC1 abrogated the ability of the IL-2-primed NK cells to produce IFN-γ in response to NKG2D-mediated stimulation. This study identifies a series of IL-2-induced cellular changes that regulates the NKG2D responsiveness in human NK cells.
[Mh] Termos MeSH primário: Sistema ASC de Transporte de Aminoácidos/metabolismo
Proteína-1 Reguladora de Fusão/metabolismo
Células Matadoras Naturais/fisiologia
Antígenos de Histocompatibilidade Menor/metabolismo
[Mh] Termos MeSH secundário: Sistema ASC de Transporte de Aminoácidos/genética
Antígeno CD56/metabolismo
Células Cultivadas
Citotoxicidade Imunológica
Seres Humanos
Interferon gama/metabolismo
Interleucina-2/imunologia
Interleucina-2/metabolismo
Ativação Linfocitária
Alvo Mecanístico do Complexo 1 de Rapamicina
Antígenos de Histocompatibilidade Menor/genética
Complexos Multiproteicos/antagonistas & inibidores
Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo
Serina-Treonina Quinases TOR/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acid Transport System ASC); 0 (CD56 Antigen); 0 (Fusion Regulatory Protein-1); 0 (Interleukin-2); 0 (KLRK1 protein, human); 0 (Minor Histocompatibility Antigens); 0 (Multiprotein Complexes); 0 (NK Cell Lectin-Like Receptor Subfamily K); 0 (SLC1A5 protein, human); 82115-62-6 (Interferon-gamma); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170809
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1700497


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[PMID]:28628108
[Au] Autor:Ma CA; Stinson JR; Zhang Y; Abbott JK; Weinreich MA; Hauk PJ; Reynolds PR; Lyons JJ; Nelson CG; Ruffo E; Dorjbal B; Glauzy S; Yamakawa N; Arjunaraja S; Voss K; Stoddard J; Niemela J; Zhang Y; Rosenzweig SD; McElwee JJ; DiMaggio T; Matthews HF; Jones N; Stone KD; Palma A; Oleastro M; Prieto E; Bernasconi AR; Dubra G; Danielian S; Zaiat J; Marti MA; Kim B; Cooper MA; Romberg N; Meffre E; Gelfand EW; Snow AL; Milner JD
[Ad] Endereço:Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
[Ti] Título:Germline hypomorphic CARD11 mutations in severe atopic disease.
[So] Source:Nat Genet;49(8):1192-1201, 2017 Aug.
[Is] ISSN:1546-1718
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Few monogenic causes for severe manifestations of common allergic diseases have been identified. Through next-generation sequencing on a cohort of patients with severe atopic dermatitis with and without comorbid infections, we found eight individuals, from four families, with novel heterozygous mutations in CARD11, which encodes a scaffolding protein involved in lymphocyte receptor signaling. Disease improved over time in most patients. Transfection of mutant CARD11 expression constructs into T cell lines demonstrated both loss-of-function and dominant-interfering activity upon antigen receptor-induced activation of nuclear factor-κB and mammalian target of rapamycin complex 1 (mTORC1). Patient T cells had similar defects, as well as low production of the cytokine interferon-γ (IFN-γ). The mTORC1 and IFN-γ production defects were partially rescued by supplementation with glutamine, which requires CARD11 for import into T cells. Our findings indicate that a single hypomorphic mutation in CARD11 can cause potentially correctable cellular defects that lead to atopic dermatitis.
[Mh] Termos MeSH primário: Proteínas Adaptadoras de Sinalização CARD/genética
Dermatite Atópica/genética
Mutação em Linhagem Germinativa
Guanilato Ciclase/genética
[Mh] Termos MeSH secundário: Sistema ASC de Transporte de Aminoácidos/metabolismo
Estudos de Coortes
Análise Mutacional de DNA
Dermatite Atópica/imunologia
Feminino
Genes Dominantes
Glutamina/metabolismo
Seres Humanos
Células Jurkat
Ativação Linfocitária
Masculino
Alvo Mecanístico do Complexo 1 de Rapamicina
Antígenos de Histocompatibilidade Menor/metabolismo
Complexos Multiproteicos/metabolismo
NF-kappa B/metabolismo
Linhagem
Linfócitos T/imunologia
Linfócitos T/metabolismo
Serina-Treonina Quinases TOR/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acid Transport System ASC); 0 (CARD Signaling Adaptor Proteins); 0 (Minor Histocompatibility Antigens); 0 (Multiprotein Complexes); 0 (NF-kappa B); 0 (SLC1A5 protein, human); 0RH81L854J (Glutamine); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1); EC 4.6.1.2 (CARD11 protein, human); EC 4.6.1.2 (Guanylate Cyclase)
[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:170620
[St] Status:MEDLINE
[do] DOI:10.1038/ng.3898


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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]:28609484
[Au] Autor:Bjersand K; Seidal T; Sundström-Poromaa I; Åkerud H; Skirnisdottir I
[Ad] Endereço:Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
[Ti] Título:The clinical and prognostic correlation of HRNPM and SLC1A5 in pathogenesis and prognosis in epithelial ovarian cancer.
[So] Source:PLoS One;12(6):e0179363, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVES: To evaluate the prognostic effect of the Heterogeneous nuclear ribonucleoprotein type M (HNRPM) and Solute carrier 1A5 (SLC1A5) in FIGO-stages I-II epithelial ovarian cancer. METHODS: A retrospective cohort study was designed to investigate the prognostic effect of HNRPM and SLC1A5, and the association with clinical-pathologic characteristics in 131 patients with FIGO-stages I-II epithelial ovarian cancer. Tissue microarrays were constructed and protein levels were assessed by immunohistochemistry (IHC). RESULTS: Positive HRNPM status was associated with positive staining for PUMA (P = 0.04), concomitant PUMA and p21 staining (P = 0.005), and VEGF-R2 (P = 0.003). Positive SLC1A5 staining was associated with positive staining of p27 (P = 0.030), PUMA (P = 0.039), concomitant PUMA and p27 staining, and VEGF-R2 (P = 0.039). In non-serous tumors (n = 72), the SLC1A5 positivity was associated with recurrent disease (P = 0.01). In a multivariable logistic regression analysis FIGO-stage (OR = 12.4), tumor grade (OR = 5.1) and SLC1A5 positivity (OR = 0.1) were independent predictive factors for recurrent disease. Disease-free survival (DFS) in women with SLC1A5-positive non-serous tumors was 92% compared with of 66% in patients with SLC1A5-negative non-serous tumors (Log-rank = 15.343; P = 0.008). In Cox analysis with DFS as endpoint, FIGO-stage (HR = 4.5) and SLC1A5 status (HR = 0.3) were prognostic factors. CONCLUSIONS: As the proteins HRNPM and SLC1A5 are associated with the cell cycle regulators p21 or p27, the apoptosis regulators PTEN and PUMA, and the VEGF-R2 it is concluded that both proteins have role in the pathogenesis of ovarian cancer. In patients with non-serous ovarian cancer SLC1A5 protects from recurrent disease, presumably by means of biological mechanisms that are unrelated to cytotoxic drug sensitivity.
[Mh] Termos MeSH primário: Sistema ASC de Transporte de Aminoácidos/metabolismo
Ribonucleoproteínas Nucleares Heterogêneas Grupo M/metabolismo
Antígenos de Histocompatibilidade Menor/metabolismo
Neoplasias Epiteliais e Glandulares/metabolismo
Neoplasias Ovarianas/metabolismo
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Proteínas Reguladoras de Apoptose/metabolismo
Biomarcadores Tumorais/metabolismo
Distribuição de Qui-Quadrado
Inibidor de Quinase Dependente de Ciclina p21/metabolismo
Inibidor de Quinase Dependente de Ciclina p27/metabolismo
Feminino
Seres Humanos
Imuno-Histoquímica
Estimativa de Kaplan-Meier
Meia-Idade
Estadiamento de Neoplasias
Neoplasias Epiteliais e Glandulares/patologia
Neoplasias Ovarianas/patologia
PTEN Fosfo-Hidrolase/metabolismo
Prognóstico
Proteínas Proto-Oncogênicas/metabolismo
Estudos Retrospectivos
Fatores de Risco
Análise Serial de Tecidos/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acid Transport System ASC); 0 (Apoptosis Regulatory Proteins); 0 (BBC3 protein, human); 0 (Biomarkers, Tumor); 0 (Cyclin-Dependent Kinase Inhibitor p21); 0 (HNRNPM protein, human); 0 (Heterogeneous-Nuclear Ribonucleoprotein Group M); 0 (Minor Histocompatibility Antigens); 0 (Proto-Oncogene Proteins); 0 (SLC1A5 protein, human); 147604-94-2 (Cyclin-Dependent Kinase Inhibitor p27); EC 3.1.3.67 (PTEN Phosphohydrolase); EC 3.1.3.67 (PTEN protein, human)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170614
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0179363


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[PMID]:28440528
[Au] Autor:Cai C; Zeng B; Zeng J; Xin H; Tang C
[Ti] Título:[Effect of ASCT2 gene knock-down by shRNA on biological behaviors of colorectal cancer cells].
[So] Source:Zhonghua Wei Chang Wai Ke Za Zhi;20(4):450-454, 2017 Apr 25.
[Is] ISSN:1671-0274
[Cp] País de publicação:China
[La] Idioma:chi
[Ab] Resumo:OBJECTIVE: To investigate the effect of ASCT2 gene (glutamine transporter) knock-down by shRNA on biological behaviors of colorectal cancer cells. METHODS: shRNA was transfected into colorectal cancer cells Lovo and SW480 to knockdown ASCT2 mediated by Lipofectamine 2000. Reverse transcription-PCR and Western blot were used to examine the mRNA and protein expression of ASCT2. MTT and transwell assay were used to determine the proliferation and invasiveness of Lovo and SW480 cells. Radioactive-tracer was used to detect the uptake of glutamine. RESULTS: ASCT2 mRNA and protein levels were significantly down-regulated by shRNA in Lovo and SW480 cells(P<0.01). MTT and transwell assays showed that ASCT2 knock-down could significantly inhibit the proliferation of Lovo and SW480 cells (A490) and decrease the number of invasive Lovo and SW480 cells from the membrane (both P<0.01). The number of membrane Lovo cells in shASCT group and control group was 46.3±5.9 and 197.7±9.1, respectively while the number of membrane SW480 cells in shASCT group and control group was 29.7±3.8 and 139.0±9.5, respectively. Radioactive-tracer showed that shASCT2 transfection could significantly reduce the uptake of glutamine, with an inhibition rate of 79.15% in Lovo and 67.22% in SW480 cells (both P<0.01). CONCLUSIONS: ASCT2 plays an oncogenic role in colonic cancer, and its promotion mechanism may be associated with glutamine metabolism. ASCT2 may be a novel therapeutic target of colonic cancer.
[Mh] Termos MeSH primário: Sistema ASC de Transporte de Aminoácidos/efeitos dos fármacos
Sistema ASC de Transporte de Aminoácidos/genética
Sistema ASC de Transporte de Aminoácidos/fisiologia
Proliferação Celular/genética
Neoplasias Colorretais/genética
Glutamina/efeitos dos fármacos
Antígenos de Histocompatibilidade Menor/efeitos dos fármacos
Antígenos de Histocompatibilidade Menor/genética
Antígenos de Histocompatibilidade Menor/fisiologia
Invasividade Neoplásica/genética
Invasividade Neoplásica/fisiopatologia
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral/fisiologia
Neoplasias Colorretais/fisiopatologia
Regulação para Baixo/efeitos dos fármacos
Técnicas de Silenciamento de Genes/métodos
Glutamina/genética
Glutamina/fisiologia
Seres Humanos
Oncogenes/efeitos dos fármacos
Oncogenes/genética
RNA Mensageiro/fisiologia
RNA Interferente Pequeno/farmacologia
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acid Transport System ASC); 0 (Minor Histocompatibility Antigens); 0 (RNA, Messenger); 0 (RNA, Small Interfering); 0 (SLC1A5 protein, human); 0RH81L854J (Glutamine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170908
[Lr] Data última revisão:
170908
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170426
[St] Status:MEDLINE


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[PMID]:28419191
[Au] Autor:Zhang W; Xu Y; Xu Q; Shi H; Shi J; Hou Y
[Ad] Endereço:Department of General Surgery, The Affiliated People's Hospital, Jiangsu University, Zhen Jiang, Jiangsu 212002, People's Republic of China.
[Ti] Título:PPARδ promotes tumor progression via activation of Glut1 and SLC1-A5 transcription.
[So] Source:Carcinogenesis;38(7):748-755, 2017 Jul 01.
[Is] ISSN:1460-2180
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Malignant cancer cell uncontrolled growth depends on the persistent nutrient availability such as glucose and amino acids, which is required for cancer cell energetic and biosynthetic pathways. As a nuclear hormone receptor, peroxisome-proliferator-activated receptor δ (PPARδ) plays a critical role in inflammation and cancer, however, it is still unclear the regulatory mechanism of PPARδ on cancer cell metabolism. Here, we found that PPARδ directly regulated neutral amino acid transporter SLC1-A5 (solute carrier family 1 member 5) and glucose transporter-1 (Glut1) gene transcription, leading to uptake of glucose and amino acid, activation of mTOR signaling, and tumor progression. In contrast, silence of PPARδ or its antagonist inhibited this event. More importantly, PPARδ promoted cancer cell metabolic reprogramming resulting in chemoresistance, which was alleviated by PPARδ antagonist. These findings revealed a novel mechanism of PPARδ-mediated tumor progression, which provided a potential strategy for cancer treatment.
[Mh] Termos MeSH primário: Sistema ASC de Transporte de Aminoácidos/genética
Transportador de Glucose Tipo 1/genética
Antígenos de Histocompatibilidade Menor/genética
Neoplasias/metabolismo
PPAR gama/genética
Serina-Treonina Quinases TOR/genética
[Mh] Termos MeSH secundário: Sistema ASC de Transporte de Aminoácidos/metabolismo
Aminoácidos/metabolismo
Animais
Vias Biossintéticas
Metabolismo Energético/genética
Glucose/metabolismo
Transportador de Glucose Tipo 1/metabolismo
Células HCT116
Seres Humanos
Inflamação/genética
Inflamação/metabolismo
Inflamação/patologia
Camundongos
Antígenos de Histocompatibilidade Menor/metabolismo
Neoplasias/genética
Neoplasias/patologia
PPAR gama/metabolismo
Transcrição Genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acid Transport System ASC); 0 (Amino Acids); 0 (Glucose Transporter Type 1); 0 (Minor Histocompatibility Antigens); 0 (PPAR gamma); 0 (SLC1A5 protein, human); 0 (SLC2A1 protein, human); EC 2.7.1.1 (TOR Serine-Threonine Kinases); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171006
[Lr] Data última revisão:
171006
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170419
[St] Status:MEDLINE
[do] DOI:10.1093/carcin/bgx035


  9 / 239 MEDLINE  
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[PMID]:28057420
[Au] Autor:Singh K; Tanui R; Gameiro A; Eisenberg G; Colas C; Schlessinger A; Grewer C
[Ad] Endereço:Department of Chemistry, Binghamton University, 4400 Vestal Pkwy East, Binghamton, NY 13902, United States.
[Ti] Título:Structure activity relationships of benzylproline-derived inhibitors of the glutamine transporter ASCT2.
[So] Source:Bioorg Med Chem Lett;27(3):398-402, 2017 02 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The glutamine transporter ASCT2 has been identified as a promising target to inhibit rapid growth of cancer cells. However, ASCT2 pharmacology is not well established. In this report, we performed a systematic structure activity analysis of a series of substituted benzylproline derivatives. Substitutions on the phenyl ring resulted in compounds with characteristics of ASCT2 inhibitors. Apparent binding affinity increased with increasing hydrophobicity of the side chain. In contrast, interaction of the ASCT2 binding site with specific positions on the phenyl ring was not observed. The most potent compound inhibits the ASCT2 anion conductance with a K of 3µM, which is in the same range as that of more bulky and higher molecular weight inhibitors recently reported by others. The experimental results are consistent with computational analysis based on docking of the inhibitors against an ASCT2 homology model. The benzylproline scaffold provides a valuable tool for further improving binding potency of future ASCT2 inhibitors.
[Mh] Termos MeSH primário: Sistema ASC de Transporte de Aminoácidos/antagonistas & inibidores
Prolina/análogos & derivados
[Mh] Termos MeSH secundário: Sistema ASC de Transporte de Aminoácidos/genética
Sistema ASC de Transporte de Aminoácidos/metabolismo
Animais
Sítios de Ligação
Células HEK293
Seres Humanos
Ligações de Hidrogênio
Simulação de Acoplamento Molecular
Prolina/metabolismo
Ligação Proteica
Estrutura Terciária de Proteína
Ratos
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Amino Acid Transport System ASC); 9DLQ4CIU6V (Proline)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171124
[Lr] Data última revisão:
171124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170107
[St] Status:MEDLINE


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[PMID]:28043791
[Au] Autor:Lee NY; Kim Y; Ryu H; Kang YS
[Ad] Endereço:College of Pharmacy and Research Center for Cell Fate Control, Sookmyung Women's University, Seoul, Republic of Korea.
[Ti] Título:The alteration of serine transporter activity in a cell line model of amyotrophic lateral sclerosis (ALS).
[So] Source:Biochem Biophys Res Commun;483(1):135-141, 2017 Jan 29.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The alteration of d-serine levels is associated with the pathogenesis of sporadic ALS and mutant SOD1 (G93A) animal model of ALS. However, the exact mechanism of d-serine transport is not known in ALS. To better understand the distribution of d-serine in ALS, we determined the activity and the expression of serine transporter in a motor neuronal cell line model of ALS (NSC-34/hSOD1 cells). The uptake of [ H]d-serine was significantly lower in NSC-34/hSOD1 cells than in control NSC-34 and NSC-34/hSOD1 cells. In contrast, the uptake of [ H]l-serine, precursor of d-serine, was markedly increased in NSC-34/hSOD1 cells compared to control NSC-34 and NSC-34/hSOD1 cells. Both [ H]d-serine and [ H]l-serine uptake were saturable in these cells. The estimated Michaelis-Menten constant, K , for d-serine uptakes was higher in NSC-34/hSOD1 cells than in NSC-34/hSOD1 cells while the K for l-serine uptake was 2 fold lower in NSC-34/hSOD1 cells than in control cells. [ H]d-serine and [ H]l-serine uptakes took place in a Na -dependent manner, and both uptakes were significantly inhibited by system ASC (alanine-serine-cysteine) substrates. As a result of small interfering RNA experiments, we found that ASCT2 (SLC1A5) and ASCT1 (SLC1A4) are involved in [ H]d-serine and [ H]l-serine uptake in NSC-34/hSOD1 cells, respectively. The level of SLC1A4 mRNA was significantly increased in NSC-34/hSOD1 compared to NSC-34 and NSC-34/hSOD1 cells. In contrast, the level of SLC7A10 mRNA was relatively lower in NSC-34/hSOD1 cells than the control cells. Together, these data suggest that the pathological alteration of d- and l-serine uptakes in ALS is driven by the affinity change of d-and l-serine uptake system.
[Mh] Termos MeSH primário: Sistema ASC de Transporte de Aminoácidos/metabolismo
Esclerose Amiotrófica Lateral/metabolismo
Neurônios Motores/metabolismo
Serina/metabolismo
[Mh] Termos MeSH secundário: Sistema ASC de Transporte de Aminoácidos/genética
Sistema y+ de Transporte de Aminoácidos/genética
Sistema y+ de Transporte de Aminoácidos/metabolismo
Esclerose Amiotrófica Lateral/genética
Animais
Linhagem Celular
Modelos Animais de Doenças
Regulação da Expressão Gênica
Técnicas de Silenciamento de Genes
Camundongos Transgênicos
Antígenos de Histocompatibilidade Menor/genética
Antígenos de Histocompatibilidade Menor/metabolismo
Neurônios Motores/patologia
Superóxido Dismutase-1/genética
Superóxido Dismutase-1/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acid Transport System ASC); 0 (Amino Acid Transport System y+); 0 (Minor Histocompatibility Antigens); 0 (SOD1 protein, human); 0 (Slc1a4 protein, mouse); 0 (Slc1a5 protein, mouse); 0 (Slc7a10 protein, mouse); 452VLY9402 (Serine); EC 1.15.1.1 (Superoxide Dismutase-1)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170601
[Lr] Data última revisão:
170601
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170104
[St] Status:MEDLINE



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