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  1 / 25217 MEDLINE  
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[PMID]:29409738
[Au] Autor:Li XP; Lan JY; Liu DQ; Zhou H; Qian MM; Wang WW; Yang M
[Ad] Endereço:Department of Laboratory Medicine, The Hospital Of Hangzhou Dianzi University, Hangzhou, Zhejiang, China.
[Ti] Título:OCA2 rs4778137 polymorphism predicts survival of breast cancer patients receiving neoadjuvant chemotherapy.
[So] Source:Gene;651:161-165, 2018 Apr 20.
[Is] ISSN:1879-0038
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Genome-wide association study (GWAS) studies have showed that single nucleotide polymorphisms (SNPs) in OCA2 gene were associated with the survival of breast cancer patients treated with adjuvant chemotherapy. To further explain the association between OCA2 SNPs and breast cancer survival, we investigated the predictive value of rs4778137 located in OCA2 in local advanced breast cancer patients receiving neoadjuvant chemotherapy. PATIENTS AND METHODS: A case-cohort with 150 breast cancer patients was performed to evaluate the effects of the OCA2 rs4778137 on breast cancer survival. The association between rs4778137 genotypes and pathological complete response (pCR, defined that the postoperative pathology indicating no residual invasive breast cancer in the breast or the axillary lymph node) were analyzed. Logistic regression analysis was performed to identify the independent predictors of pCR. Survival was assessed by Kaplan-Meier method and Cox regression analysis according to the rs4778137 genotypes. RESULTS: The differences between pCR and the rs4778137 genotypes were statistically significant (p < 0.05). The patients with genotype GG harbored a better disease-free survival (HR: 2.358, p = 0.000) and overall survival (HR: 1.578, p = 0.008) than the patients with genotype CC in rs4778137. The further Univariate and Multivariate survival analysis revealed that SNP rs4778137 was an independent predictive factor of disease-free survival (p = 0.000/p = 0.001) and overall survival (p = 0.006/p = 0.045). CONCLUSION: The OCA2 rs4778137 may be a predictor for the clinical response and survival in local advanced breast cancer patients who received neoadjuvant chemotherapy.
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Neoplasias da Mama/genética
Neoplasias da Mama/terapia
Proteínas de Membrana Transportadoras/genética
Terapia Neoadjuvante
Polimorfismo de Nucleotídeo Único
[Mh] Termos MeSH secundário: Adulto
Neoplasias da Mama/mortalidade
Quimioterapia Adjuvante
Estudos de Coortes
Terapia Combinada
Epirubicina/uso terapêutico
Feminino
Seguimentos
Seres Humanos
Meia-Idade
Prognóstico
Análise de Sobrevida
Taxoides/uso terapêutico
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Membrane Transport Proteins); 0 (OCA2 protein, human); 0 (Taxoids); 3Z8479ZZ5X (Epirubicin)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180208
[St] Status:MEDLINE


  2 / 25217 MEDLINE  
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[PMID]:29324833
[Au] Autor:Lyte M; Brown DR
[Ad] Endereço:Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, Iowa, United States of America.
[Ti] Título:Evidence for PMAT- and OCT-like biogenic amine transporters in a probiotic strain of Lactobacillus: Implications for interkingdom communication within the microbiota-gut-brain axis.
[So] Source:PLoS One;13(1):e0191037, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The ability of prokaryotic microbes to produce and respond to neurochemicals that are more often associated with eukaryotic systems is increasingly recognized through the concept of microbial endocrinology. Most studies have described the phenomena of neurochemical production by bacteria, but there remains an incomplete understanding of the mechanisms by which microbe- or host-derived neuroactive substances can be recognized by bacteria. Based on the evolutionary origins of eukaryotic solute carrier transporters, we hypothesized that bacteria may possess an analogous uptake function for neuroactive biogenic amines. Using specific fluorescence-based assays, Lactobacillus salivarius biofilms appear to express both plasma membrane monoamine transporter (PMAT)- and organic cation transporter (OCT)-like uptake of transporter-specific fluorophores. This phenomenon is not distributed throughout the genus Lactobacillus as L. rhamnosus biofilms did not take up these fluorophores. PMAT probe uptake into L. salivarius biofilms was attenuated by the protonophore CCCP, the cation transport inhibitor decynium-22, and the natural substrates norepinephrine, serotonin and fluoxetine. These results provide the first evidence, to our knowledge, for the existence of PMAT- and OCT-like uptake systems in a bacterium. They also suggest the existence of a hitherto unrecognized mechanism by which a probiotic bacterium may interact with host signals and may provide a means to examine microbial endocrinology-based interactions in health and disease that are part of the larger microbiota-gut-brain axis.
[Mh] Termos MeSH primário: Aminas Biogênicas/metabolismo
Proteínas de Membrana Transportadoras/metabolismo
Probióticos
[Mh] Termos MeSH secundário: Biofilmes
Espectrometria de Fluorescência
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Biogenic Amines); 0 (Membrane Transport Proteins)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180112
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191037


  3 / 25217 MEDLINE  
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[PMID]:28461451
[Au] Autor:Li L; Jiang W; Lu Y
[Ad] Endereço:Key Laboratory of Synthetic Biology, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
[Ti] Título:A Novel Two-Component System, GluR-GluK, Involved in Glutamate Sensing and Uptake in Streptomyces coelicolor.
[So] Source:J Bacteriol;199(18), 2017 09 15.
[Is] ISSN:1098-5530
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Two-component systems (TCSs), the predominant signal transduction pathways employed by bacteria, play important roles in physiological metabolism in Here, a novel TCS, GluR-GluK (encoded by ), which is located divergently from the operon encoding a glutamate uptake system, was identified as being involved in glutamate sensing and uptake as well as antibiotic biosynthesis in Under the condition of minimal medium (MM) supplemented with different concentrations of glutamate, deletion of the operon ( ) resulted in enhanced actinorhodin (ACT) but reduced undecylprodigiosin (RED) and yellow type I polyketide (yCPK) production, suggesting that GluR-GluK plays a differential role in antibiotic biosynthesis. Furthermore, we found that the response regulator GluR directly promotes the expression of under the culture condition of MM with a high concentration of glutamate (75 mM). Using the biolayer interferometry assay, we demonstrated that glutamate acts as the direct signal of the histidine kinase GluK. It was therefore suggested that upon sensing high concentrations of glutamate, GluR-GluK would be activated and thereby facilitate glutamate uptake by increasing expression. Finally, we demonstrated that the role of GluR-GluK in antibiotic biosynthesis is independent of its function in glutamate uptake. Considering the wide distribution of the glutamate-sensing (GluR-GluK) and uptake (GluABCD) module in actinobacteria, it could be concluded that the GluR-GluK signal transduction pathway involved in secondary metabolism and glutamate uptake should be highly conserved in this bacterial phylum. In this study, a novel two-component system (TCS), GluR-GluK, was identified to be involved in glutamate sensing and uptake as well as antibiotic biosynthesis in A possible GluR-GluK working model was proposed. Upon sensing high glutamate concentrations (such as 75 mM), activated GluR-GluK could regulate both glutamate uptake and antibiotic biosynthesis. However, under a culture condition of MM supplemented with low concentrations of glutamate (such as 10 mM), although GluR-GluK is activated, its activity is sufficient only for the regulation of antibiotic biosynthesis. To the best of our knowledge, this is the first report describing a TCS signal transduction pathway for glutamate sensing and uptake in actinobacteria.
[Mh] Termos MeSH primário: Ácido Glutâmico/metabolismo
Histidina Quinase/metabolismo
Transdução de Sinais
Streptomyces coelicolor/metabolismo
Fatores de Transcrição/metabolismo
[Mh] Termos MeSH secundário: Transporte Biológico
Meios de Cultura/química
Deleção de Genes
Regulação da Expressão Gênica
Histidina Quinase/genética
Proteínas de Membrana Transportadoras/genética
Proteínas de Membrana Transportadoras/metabolismo
Óperon
Streptomyces coelicolor/genética
Fatores de Transcrição/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Culture Media); 0 (Membrane Transport Proteins); 0 (Transcription Factors); 3KX376GY7L (Glutamic Acid); EC 2.7.13.1 (Histidine Kinase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:180306
[Lr] Data última revisão:
180306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE


  4 / 25217 MEDLINE  
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[PMID]:28461447
[Au] Autor:Hoffmann MC; Pfänder Y; Tintel M; Masepohl B
[Ad] Endereço:Biologie der Mikroorganismen, Fakultät für Biologie und Biotechnologie, Ruhr-Universität Bochum, Bochum, Germany.
[Ti] Título:Bacterial PerO Permeases Transport Sulfate and Related Oxyanions.
[So] Source:J Bacteriol;199(14), 2017 07 15.
[Is] ISSN:1098-5530
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:synthesizes the high-affinity ABC transporters CysTWA and ModABC to specifically import the chemically related oxyanions sulfate and molybdate, respectively. In addition, has the low-affinity permease PerO acting as a general oxyanion transporter, whose elimination increases tolerance to molybdate and tungstate. Although PerO-like permeases are widespread in bacteria, their function has not been examined in any other species to date. Here, we present evidence that PerO permeases from the alphaproteobacteria , , , and and the gammaproteobacterium functionally substitute for PerO in sulfate uptake and sulfate-dependent growth, as shown by assimilation of radioactively labeled sulfate and heterologous complementation. Disruption of genes in , , and increased tolerance to tungstate and, in the case of , to molybdate, suggesting that heterometal oxyanions are common substrates of PerO permeases. This study supports the view that bacterial PerO permeases typically transport sulfate and related oxyanions and, hence, form a functionally conserved permease family. Despite the widespread distribution of PerO-like permeases in bacteria, our knowledge about PerO function until now was limited to one species, In this study, we showed that PerO proteins from diverse bacteria are functionally similar to the prototype, suggesting that PerO permeases form a conserved family whose members transport sulfate and related oxyanions.
[Mh] Termos MeSH primário: Proteínas de Bactérias/metabolismo
Proteínas de Membrana Transportadoras/metabolismo
Rhodobacter capsulatus/enzimologia
Sulfatos/metabolismo
[Mh] Termos MeSH secundário: Ânions/metabolismo
Proteínas de Bactérias/genética
Transporte Biológico/fisiologia
Regulação Bacteriana da Expressão Gênica/fisiologia
Regulação Enzimológica da Expressão Gênica/fisiologia
Proteínas de Membrana Transportadoras/genética
Mutação
Rhodobacter capsulatus/genética
Rhodobacter capsulatus/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anions); 0 (Bacterial Proteins); 0 (Membrane Transport Proteins); 0 (Sulfates)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:180306
[Lr] Data última revisão:
180306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE


  5 / 25217 MEDLINE  
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[PMID]:29323112
[Au] Autor:Pflüger T; Hernández CF; Lewe P; Frank F; Mertens H; Svergun D; Baumstark MW; Lunin VY; Jetten MSM; Andrade SLA
[Ad] Endereço:Institute for Biochemistry, University of Freiburg, Albertstr. 21, Freiburg, 79104, Germany.
[Ti] Título:Signaling ammonium across membranes through an ammonium sensor histidine kinase.
[So] Source:Nat Commun;9(1):164, 2018 01 11.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Sensing and uptake of external ammonium is essential for anaerobic ammonium-oxidizing (anammox) bacteria, and is typically the domain of the ubiquitous Amt/Rh ammonium transporters. Here, we report on the structure and function of an ammonium sensor/transducer from the anammox bacterium "Candidatus Kuenenia stuttgartiensis" that combines a membrane-integral ammonium transporter domain with a fused histidine kinase. It contains a high-affinity ammonium binding site not present in assimilatory Amt proteins. The levels of phosphorylated histidine in the kinase are coupled to the presence of ammonium, as conformational changes during signal recognition by the Amt module are transduced internally to modulate the kinase activity. The structural analysis of this ammonium sensor by X-ray crystallography and small-angle X-ray-scattering reveals a flexible, bipartite system that recruits a large uptake transporter as a sensory module and modulates its functionality to achieve a mechanistic coupling to a kinase domain in order to trigger downstream signaling events.
[Mh] Termos MeSH primário: Compostos de Amônio/metabolismo
Proteínas de Bactérias/metabolismo
Membrana Celular/metabolismo
Histidina Quinase/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Compostos de Amônio/química
Bactérias/genética
Bactérias/metabolismo
Proteínas de Bactérias/genética
Sítios de Ligação/genética
Cristalografia por Raios X
Histidina Quinase/química
Histidina Quinase/genética
Proteínas de Membrana Transportadoras/química
Proteínas de Membrana Transportadoras/genética
Proteínas de Membrana Transportadoras/metabolismo
Modelos Moleculares
Oxirredução
Ligação Proteica
Domínios Proteicos
Espalhamento a Baixo Ângulo
Homologia de Sequência de Aminoácidos
Difração de Raios X
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Ammonium Compounds); 0 (Bacterial Proteins); 0 (Membrane Transport Proteins); EC 2.7.13.1 (Histidine Kinase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180112
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02637-3


  6 / 25217 MEDLINE  
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[PMID]:28454702
[Au] Autor:Ellery SJ; Della Gatta PA; Bruce CR; Kowalski GM; Davies-Tuck M; Mockler JC; Murthi P; Walker DW; Snow RJ; Dickinson H
[Ad] Endereço:The Ritchie Centre, Hudson Institute of Medical Research, Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia.
[Ti] Título:Creatine biosynthesis and transport by the term human placenta.
[So] Source:Placenta;52:86-93, 2017 Apr.
[Is] ISSN:1532-3102
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Creatine is an amino acid derivative that is involved in preserving ATP homeostasis. Previous studies suggest an important role for the creatine kinase circuit for placental ATP turnover. Creatine is obtained from both the diet and endogenous synthesis, usually along the renal-hepatic axis. However, some tissues with a high-energy demand have an inherent capacity to synthesise creatine. In this study, we determined if the term human placenta has the enzymatic machinary to synthesise creatine. METHODS: Eleven placentae were collected following elective term caesarean section. Samples from the 4 quadrants of each placenta were either fixed in formalin or frozen. qPCR was used to determine the mRNA expression of the creatine synthesising enzymes arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT), and the creatine transporter (SLC6A8). Protein expression of AGAT and GAMT was quantified by Western blot, and observations of cell localisation of AGAT, GAMT and SLC6A8 made with immunohistochemistry. Synthesis of guanidinoacetate (GAA; creatine precursor) and creatine in placental homogenates was determined via GC-MS and HPLC, respectively. RESULTS: AGAT, GAMT and SLC6A8 mRNA and protein were detected in the human placenta. AGAT staining was identified in stromal and endothelial cells of the fetal capillaries. GAMT and SLC6A8 staining was localised to the syncytiotrophoblast of the fetal villi. Ex vivo, tissue homogenates produce both GAA (4.6 nmol mg protein h ) and creatine (52.8 nmol mg protein h ). DISCUSSION: The term human placenta has the capacity to synthesise creatine. These data present a new understanding of placental energy metabolism.
[Mh] Termos MeSH primário: Amidinotransferases/metabolismo
Creatina/metabolismo
Guanidinoacetato N-Metiltransferase/metabolismo
Proteínas de Membrana Transportadoras/metabolismo
Placenta/metabolismo
[Mh] Termos MeSH secundário: Transporte Biológico
Creatina/biossíntese
Células Endoteliais/metabolismo
Metabolismo Energético/fisiologia
Feminino
Seres Humanos
Gravidez
Células Estromais/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Membrane Transport Proteins); 0 (creatine transporter); EC 2.1.1.2 (GAMT protein, human); EC 2.1.1.2 (Guanidinoacetate N-Methyltransferase); EC 2.1.4.- (Amidinotransferases); EC 2.1.4.1 (glycine amidinotransferase); MU72812GK0 (Creatine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE


  7 / 25217 MEDLINE  
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[PMID]:29212662
[Au] Autor:Chatterjee K; Majumder S; Wan Y; Shah V; Wu J; Huang HY; Hopper AK
[Ad] Endereço:The Ohio State University Comprehensive Cancer Research Center, The Ohio State University, Columbus, Ohio 43210, USA.
[Ti] Título:Sharing the load: Mex67-Mtr2 cofunctions with Los1 in primary tRNA nuclear export.
[So] Source:Genes Dev;31(21):2186-2198, 2017 11 01.
[Is] ISSN:1549-5477
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Eukaryotic transfer RNAs (tRNAs) are exported from the nucleus, their site of synthesis, to the cytoplasm, their site of function for protein synthesis. The evolutionarily conserved ß-importin family member Los1 (Exportin-t) has been the only exporter known to execute nuclear export of newly transcribed intron-containing pre-tRNAs. Interestingly, is unessential in all tested organisms. As tRNA nuclear export is essential, we previously interrogated the budding yeast proteome to identify candidates that function in tRNA nuclear export. Here, we provide molecular, genetic, cytological, and biochemical evidence that the Mex67-Mtr2 (TAP-p15) heterodimer, best characterized for its essential role in mRNA nuclear export, cofunctions with Los1 in tRNA nuclear export. Inactivation of Mex67 or Mtr2 leads to rapid accumulation of end-matured unspliced tRNAs in the nucleus. Remarkably, merely fivefold overexpression of Mex67-Mtr2 can substitute for Los1 in Δ cells. Moreover, in vivo coimmunoprecipitation assays with tagged Mex67 document that the Mex67 binds tRNAs. Our data also show that tRNA exporters surprisingly exhibit differential tRNA substrate preferences. The existence of multiple tRNA exporters, each with different tRNA preferences, may indicate that the proteome can be regulated by tRNA nuclear export. Thus, our data show that Mex67-Mtr2 functions in primary nuclear export for a subset of yeast tRNAs.
[Mh] Termos MeSH primário: Transporte Ativo do Núcleo Celular/genética
Proteoma/genética
RNA de Transferência/metabolismo
Proteínas de Saccharomyces cerevisiae/genética
Proteínas de Saccharomyces cerevisiae/metabolismo
Saccharomyces cerevisiae/genética
Saccharomyces cerevisiae/metabolismo
[Mh] Termos MeSH secundário: Inativação Gênica
Proteínas de Membrana Transportadoras/genética
Proteínas de Membrana Transportadoras/metabolismo
Complexo de Proteínas Formadoras de Poros Nucleares/genética
Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo
Proteínas Nucleares/genética
Proteínas Nucleares/metabolismo
Proteínas de Transporte Nucleocitoplasmático/genética
Proteínas de Transporte Nucleocitoplasmático/metabolismo
Ligação Proteica
Proteínas de Ligação a RNA/genética
Proteínas de Ligação a RNA/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Los1 protein, S cerevisiae); 0 (MEX67 protein, S cerevisiae); 0 (Membrane Transport Proteins); 0 (Mtr2 protein, S cerevisiae); 0 (Nuclear Pore Complex Proteins); 0 (Nuclear Proteins); 0 (Nucleocytoplasmic Transport Proteins); 0 (Proteome); 0 (RNA-Binding Proteins); 0 (Saccharomyces cerevisiae Proteins); 9014-25-9 (RNA, Transfer)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171208
[St] Status:MEDLINE
[do] DOI:10.1101/gad.305904.117


  8 / 25217 MEDLINE  
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[PMID]:29248133
[Au] Autor:Mikkilineni L; Whitaker-Menezes D; Domingo-Vidal M; Sprandio J; Avena P; Cotzia P; Dulau-Florea A; Gong J; Uppal G; Zhan T; Leiby B; Lin Z; Pro B; Sotgia F; Lisanti MP; Martinez-Outschoorn U
[Ad] Endereço:Department of Medical Oncology, National Cancer Institute, Bethesda, MD.
[Ti] Título:Hodgkin lymphoma: A complex metabolic ecosystem with glycolytic reprogramming of the tumor microenvironment.
[So] Source:Semin Oncol;44(3):218-225, 2017 06.
[Is] ISSN:1532-8708
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Twenty percent of patients with classical Hodgkin Lymphoma (cHL) have aggressive disease defined as relapsed or refractory disease to initial therapy. At present we cannot identify these patients pre-treatment. The microenvironment is very important in cHL because non-cancer cells constitute the majority of the cells in these tumors. Non-cancer intra-tumoral cells, such as tumor-associated macrophages (TAMs) have been shown to promote tumor growth in cHL via crosstalk with the cancer cells. Metabolic heterogeneity is defined as high mitochondrial metabolism in some tumor cells and glycolysis in others. We hypothesized that there are metabolic differences between cancer cells and non-cancer tumor cells, such as TAMs and tumor-infiltrating lymphocytes in cHL and that greater metabolic differences between cancer cells and TAMs are associated with poor outcomes. METHODS: A case-control study was conducted with 22 tissue samples of cHL at diagnosis from a single institution. The case samples were from 11 patients with aggressive cHL who had relapsed after standard treatment with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) or were refractory to this treatment. The control samples were from 11 patients with cHL who achieved a remission and never relapsed after ABVD. Reactive non-cancerous lymph nodes from four subjects served as additional controls. Samples were stained by immunohistochemistry for three metabolic markers: translocase of the outer mitochondrial membrane 20 (TOMM20), monocarboxylate transporter 1 (MCT1), and monocarboxylate transporter 4 (MCT4). TOMM20 is a marker of mitochondrial oxidative phosphorylation (OXPHOS) metabolism. Monocarboxylate transporter 1 (MCT1) is the main importer of lactate into cells and is a marker of OXPHOS. Monocarboxylate transporter 4 (MCT4) is the main lactate exporter out of cells and is a marker of glycolysis. The immunoreactivity for TOMM20, MCT1, and MCT4 was scored based on staining intensity and percentage of positive cells, as follows: 0 for no detectable staining in > 50% of cells; 1+ for faint to moderate staining in > 50% of cells, and 2+ for high or strong staining in > 50% of cells. RESULTS: TOMM20, MCT1, and MCT4 expression was significantly different in Hodgkin and Reed Sternberg (HRS) cells, which are the cancerous cells in cHL compared with TAMs and tumor-associated lymphocytes. HRS have high expression of TOMM20 and MCT1, while TAMs have absent expression of TOMM20 and MCT1 in all but two cases. Tumor-infiltrating lymphocytes have low TOMM20 expression and absent MCT1 expression. Conversely, high MCT4 expression was found in TAMs, but absent in HRS cells in all but one case. Tumor-infiltrating lymphocytes had absent MCT4 expression. Reactive lymph nodes in contrast to cHL tumors had low TOMM20, MCT1, and MCT4 expression in lymphocytes and macrophages. High TOMM20 and MCT1 expression in cancer cells with high MCT4 expression in TAMs is a signature of high metabolic heterogeneity between cancer cells and the tumor microenvironment. A high metabolic heterogeneity signature was associated with relapsed or refractory cHL with a hazard ratio of 5.87 (1.16-29.71; two-sided P < .05) compared with the low metabolic heterogeneity signature. CONCLUSION: Aggressive cHL exhibits features of metabolic heterogeneity with high mitochondrial metabolism in cancer cells and high glycolysis in TAMs, which is not seen in reactive lymph nodes. Future studies will need to confirm the value of these markers as prognostic and predictive biomarkers in clinical practice. Treatment intensity may be tailored in the future to the metabolic profile of the tumor microenvironment and drugs that target metabolic heterogeneity may be valuable in this disease.
[Mh] Termos MeSH primário: Glicólise
Doença de Hodgkin/metabolismo
Proteínas de Membrana Transportadoras/metabolismo
Mitocôndrias/metabolismo
Transportadores de Ácidos Monocarboxílicos/metabolismo
Recidiva Local de Neoplasia/metabolismo
Fosforilação Oxidativa
Receptores de Superfície Celular/metabolismo
Células de Reed-Sternberg/metabolismo
Simportadores/metabolismo
Microambiente Tumoral
[Mh] Termos MeSH secundário: Adulto
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Bleomicina/administração & dosagem
Estudos de Casos e Controles
Dacarbazina/administração & dosagem
Doxorrubicina/administração & dosagem
Feminino
Doença de Hodgkin/tratamento farmacológico
Seres Humanos
Imuno-Histoquímica
Linfócitos do Interstício Tumoral/metabolismo
Macrófagos/metabolismo
Masculino
Meia-Idade
Proteínas Musculares/metabolismo
Indução de Remissão
Vimblastina/administração & dosagem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Membrane Transport Proteins); 0 (Monocarboxylic Acid Transporters); 0 (Muscle Proteins); 0 (Receptors, Cell Surface); 0 (SLC16A4 protein, human); 0 (Symporters); 0 (TOMM20 protein, human); 0 (monocarboxylate transport protein 1); 11056-06-7 (Bleomycin); 5V9KLZ54CY (Vinblastine); 7GR28W0FJI (Dacarbazine); 80168379AG (Doxorubicin)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171218
[St] Status:MEDLINE


  9 / 25217 MEDLINE  
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[PMID]:29248132
[Au] Autor:Gooptu M; Whitaker-Menezes D; Sprandio J; Domingo-Vidal M; Lin Z; Uppal G; Gong J; Fratamico R; Leiby B; Dulau-Florea A; Caro J; Martinez-Outschoorn U
[Ad] Endereço:Department of Medical Oncology, Dana Farber Cancer Institute, Harvard University Medical School, Boston, MA.
[Ti] Título:Mitochondrial and glycolytic metabolic compartmentalization in diffuse large B-cell lymphoma.
[So] Source:Semin Oncol;44(3):204-217, 2017 06.
[Is] ISSN:1532-8708
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Metabolic heterogeneity between neoplastic cells and surrounding stroma has been described in several epithelial malignancies; however, the metabolic phenotypes of neoplastic lymphocytes and neighboring stroma in diffuse large B-cell lymphoma (DLBCL) is unknown. We investigated the metabolic phenotypes of human DLBCL tumors by using immunohistochemical markers of glycolytic and mitochondrial oxidative phosphorylation (OXPHOS) metabolism. The lactate importer MCT4 is a marker of glycolysis, whereas the lactate importer MCT1 and TOMM20 are markers of OXPHOS metabolism. Staining patterns were assessed in 33 DLBCL samples as well as 18 control samples (non-neoplastic lymph nodes). TOMM20 and MCT1 were highly expressed in neoplastic lymphocytes, indicating an OXPHOS phenotype, whereas non-neoplastic lymphocytes in the control samples did not express these markers. Stromal cells in DLBCL samples strongly expressed MCT4, displaying a glycolytic phenotype, a feature not seen in stromal elements of non-neoplastic lymphatic tissue. Furthermore, the differential expression of lactate exporters (MCT4) on tumor-associated stroma and lactate importers (MCT1) on neoplastic lymphocytes support the hypothesis that neoplastic cells are metabolically linked to the stroma likely via mutually beneficial reprogramming. MCT4 is a marker of tumor-associated stroma in neoplastic tissue. Our findings suggest that disruption of neoplastic-stromal cell metabolic heterogeneity including MCT1 and MCT4 blockade should be studied to determine if it could represent a novel treatment target in DLBCL.
[Mh] Termos MeSH primário: Glicólise
Linfoma Difuso de Grandes Células B/metabolismo
Mitocôndrias/metabolismo
Fosforilação Oxidativa
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Estudos de Casos e Controles
Feminino
Seres Humanos
Imuno-Histoquímica
Linfócitos/metabolismo
Masculino
Proteínas de Membrana Transportadoras/metabolismo
Meia-Idade
Transportadores de Ácidos Monocarboxílicos/metabolismo
Proteínas Musculares/metabolismo
Receptores de Superfície Celular/metabolismo
Células Estromais/metabolismo
Simportadores/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Membrane Transport Proteins); 0 (Monocarboxylic Acid Transporters); 0 (Muscle Proteins); 0 (Receptors, Cell Surface); 0 (SLC16A4 protein, human); 0 (Symporters); 0 (TOMM20 protein, human); 0 (monocarboxylate transport protein 1)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171218
[St] Status:MEDLINE


  10 / 25217 MEDLINE  
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[PMID]:28465296
[Au] Autor:Nyquist MD; Corella A; Burns J; Coleman I; Gao S; Tharakan R; Riggan L; Cai C; Corey E; Nelson PS; Mostaghel EA
[Ad] Endereço:Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington.
[Ti] Título:Exploiting AR-Regulated Drug Transport to Induce Sensitivity to the Survivin Inhibitor YM155.
[So] Source:Mol Cancer Res;15(5):521-531, 2017 05.
[Is] ISSN:1557-3125
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Androgen receptor (AR) signaling is fundamental to prostate cancer and is the dominant therapeutic target in metastatic disease. However, stringent androgen deprivation therapy regimens decrease quality of life and have been largely unsuccessful in curtailing mortality. Recent clinical and preclinical studies have taken advantage of the dichotomous ability of AR signaling to elicit growth-suppressive and differentiating effects by administering hyperphysiologic levels of testosterone. In this study, high-throughput drug screening identified a potent synergy between high-androgen therapy and YM155, a transcriptional inhibitor of survivin (BIRC5). This interaction was mediated by the direct transcriptional upregulation of the YM155 transporter SLC35F2 by the AR. Androgen-mediated YM155-induced cell death was completely blocked by the overexpression of multidrug resistance transporter ABCB1. SLC35F2 expression was significantly correlated with intratumor androgen levels in four distinct patient-derived xenograft models, and with AR activity score in a large gene expression dataset of castration-resistant metastases. A subset of tumors had significantly elevated SLC35F2 expression and, therefore, may identify patients who are highly responsive to YM155 treatment. IMPLICATIONS: The combination of androgen therapy with YM155 represents a novel drug synergy, and SLC35F2 may serve as a clinical biomarker of response to YM155.
[Mh] Termos MeSH primário: Androgênios/administração & dosagem
Imidazóis/administração & dosagem
Proteínas de Membrana Transportadoras/genética
Naftoquinonas/administração & dosagem
Neoplasias da Próstata/tratamento farmacológico
Receptores Androgênicos/metabolismo
[Mh] Termos MeSH secundário: Androgênios/farmacologia
Animais
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Sinergismo Farmacológico
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Imidazóis/farmacologia
Masculino
Camundongos
Naftoquinonas/farmacologia
Neoplasias da Próstata/genética
Neoplasias da Próstata/metabolismo
Transdução de Sinais/efeitos dos fármacos
Testosterona/administração & dosagem
Testosterona/farmacologia
Resultado do Tratamento
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AR protein, human); 0 (Androgens); 0 (Imidazoles); 0 (Membrane Transport Proteins); 0 (Naphthoquinones); 0 (Receptors, Androgen); 0 (SLC35F2 protein, human); 0 (YM 155); 3XMK78S47O (Testosterone)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180221
[Lr] Data última revisão:
180221
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1158/1541-7786.MCR-16-0315-T



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