Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.641
Filtrar
1.
Nat Cell Biol ; 22(4): 476-486, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32231310

RESUMO

SLC7A11-mediated cystine uptake is critical for maintaining redox balance and cell survival. Here we show that this comes at a significant cost for cancer cells with high levels of SLC7A11. Actively importing cystine is potentially toxic due to its low solubility, forcing cancer cells with high levels of SLC7A11 (SLC7A11high) to constitutively reduce cystine to the more soluble cysteine. This presents a significant drain on the cellular NADPH pool and renders such cells dependent on the pentose phosphate pathway. Limiting glucose supply to SLC7A11high cancer cells results in marked accumulation of intracellular cystine, redox system collapse and rapid cell death, which can be rescued by treatments that prevent disulfide accumulation. We further show that inhibitors of glucose transporters selectively kill SLC7A11high cancer cells and suppress SLC7A11high tumour growth. Our results identify a coupling between SLC7A11-associated cystine metabolism and the pentose phosphate pathway, and uncover an accompanying metabolic vulnerability for therapeutic targeting in SLC7A11high cancers.


Assuntos
Sistema y+ de Transporte de Aminoácidos/genética , Carcinoma de Células Renais/genética , Cistina/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/genética , Via de Pentose Fosfato/genética , Sistema y+ de Transporte de Aminoácidos/antagonistas & inibidores , Sistema y+ de Transporte de Aminoácidos/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/secundário , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Dissulfetos/metabolismo , Fármacos Gastrointestinais/farmacologia , Glucose/deficiência , Transportador de Glucose Tipo 1/antagonistas & inibidores , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Transportador de Glucose Tipo 3/antagonistas & inibidores , Transportador de Glucose Tipo 3/genética , Transportador de Glucose Tipo 3/metabolismo , Glucosefosfato Desidrogenase/genética , Glucosefosfato Desidrogenase/metabolismo , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Camundongos , Camundongos Nus , Fosfogluconato Desidrogenase/genética , Fosfogluconato Desidrogenase/metabolismo , Pirazóis/farmacologia , Quinolinas/farmacologia , Estresse Fisiológico , Sulfassalazina/farmacologia , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Nat Commun ; 11(1): 708, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024842

RESUMO

The metabolic switch from oxidative phosphorylation to glycolysis is required for tumorigenesis in order to provide cancer cells with energy and substrates of biosynthesis. Therefore, it is important to elucidate mechanisms controlling the cancer metabolic switch. MTR4 is a RNA helicase associated with a nuclear exosome that plays key roles in RNA processing and surveillance. We demonstrate that MTR4 is frequently overexpressed in hepatocellular carcinoma (HCC) and is an independent diagnostic marker predicting the poor prognosis of HCC patients. MTR4 drives cancer metabolism by ensuring correct alternative splicing of pre-mRNAs of critical glycolytic genes such as GLUT1 and PKM2. c-Myc binds to the promoter of the MTR4 gene and is important for MTR4 expression in HCC cells, indicating that MTR4 is a mediator of the functions of c-Myc in cancer metabolism. These findings reveal important roles of MTR4 in the cancer metabolic switch and present MTR4 as a promising therapeutic target for treating HCC.


Assuntos
Processamento Alternativo , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , RNA Helicases/genética , Idoso , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Genes myc , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Glicólise/fisiologia , Ribonucleoproteínas Nucleares Heterogêneas/genética , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos SCID , Pessoa de Meia-Idade , Proteína de Ligação a Regiões Ricas em Polipirimidinas/genética , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , Regiões Promotoras Genéticas , RNA Helicases/metabolismo , Hormônios Tireóideos/genética , Hormônios Tireóideos/metabolismo
3.
DNA Cell Biol ; 39(4): 631-644, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32096653

RESUMO

Lung adenocarcinoma (LUAD) accounts for an increasing proportion of non-small-cell lung cancer and an increasing number of cancer-related deaths worldwide. However, few biomarkers are available for prognosis and patient stratification. In all eight datasets from the Oncomine and The Cancer Genome Atlas (TCGA) LUAD cohorts, solute carrier family 2 member 1 (SLC2A1) was significantly more highly expressed in LUAD tissue than in normal lung tissue. High SLC2A1 expression was also significantly (p < 0.05) associated with a poor prognosis in stage I, II, and III subgroups using the Kaplan-Meier plotter. In the National Cancer Center of China (NCC) cohort, SLC2A1 expression correlated significantly (p < 0.05) with several parameters, including sex, smoking history, tumor size, tumor differentiation, T stage, N stage, and pathologic TNM stage. Moreover, multivariate Cox regression indicated SLC2A1 to be an independent prognostic factor (p < 0.05) in both TCGA and NCC cohorts. Eleven hallmark pathways were significantly enriched (p < 0.01, false discovery rate <0.25) in the high-SLC2A1 expression group. SLC2A1 is a promising biomarker that can be used to predict the prognosis of LUAD.


Assuntos
Adenocarcinoma de Pulmão/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Transportador de Glucose Tipo 1/genética , Neoplasias Pulmonares/genética , Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Transportador de Glucose Tipo 1/metabolismo , Humanos , Imuno-Histoquímica , Pulmão/patologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise Serial de Tecidos
4.
Nat Commun ; 11(1): 42, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31896748

RESUMO

DNA damage and metabolic disorders are intimately linked with premature disease onset but the underlying mechanisms remain poorly understood. Here, we show that persistent DNA damage accumulation in tissue-infiltrating macrophages carrying an ERCC1-XPF DNA repair defect (Er1F/-) triggers Golgi dispersal, dilation of endoplasmic reticulum, autophagy and exosome biogenesis leading to the secretion of extracellular vesicles (EVs) in vivo and ex vivo. Macrophage-derived EVs accumulate in Er1F/- animal sera and are secreted in macrophage media after DNA damage. The Er1F/- EV cargo is taken up by recipient cells leading to an increase in insulin-independent glucose transporter levels, enhanced cellular glucose uptake, higher cellular oxygen consumption rate and greater tolerance to glucose challenge in mice. We find that high glucose in EV-targeted cells triggers pro-inflammatory stimuli via mTOR activation. This, in turn, establishes chronic inflammation and tissue pathology in mice with important ramifications for DNA repair-deficient, progeroid syndromes and aging.


Assuntos
Dano ao DNA/fisiologia , Exossomos/metabolismo , Macrófagos/citologia , Animais , Reparo do DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Endonucleases/genética , Endonucleases/metabolismo , Exossomos/patologia , Regulação da Expressão Gênica , Glucose/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Macrófagos/metabolismo , Masculino , Camundongos Transgênicos , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/metabolismo
5.
Chem Commun (Camb) ; 56(7): 1070-1073, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31872832

RESUMO

A C1-type d-glucose-conjugated fluorescent probe Glu-1-O-DCSN was synthesized and showed deep-red emission at 685 nm with a Stokes shift of up to 150 nm in DMSO. In in vitro live cell imaging, Glu-1-O-DCSN exhibited similar and competitive uptake behaviours to d-glucose and was selectively located in mitochondria. Furthermore, Glu-1-O-DCSN was successfully employed for in vivo hypermetabolic tumor targeting.


Assuntos
Compostos de Benzilideno/química , Corantes Fluorescentes/química , Glucose/metabolismo , Glucosídeos/química , Neoplasias/diagnóstico , Animais , Compostos de Benzilideno/síntese química , Compostos de Benzilideno/toxicidade , Técnicas Biossensoriais/métodos , Linhagem Celular Tumoral , Feminino , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Transportador de Glucose Tipo 1/metabolismo , Glucosídeos/síntese química , Glucosídeos/toxicidade , Humanos , Camundongos Nus , Mitocôndrias/metabolismo , Neoplasias/metabolismo
6.
Toxicol Lett ; 318: 1-11, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31618665

RESUMO

Triptolide (TP), a principal bioactive component extracted from traditional Chinese medicine Tripterygium wilfordii Hook. F. (TWHF), has attracted wide attention of its therapeutic effects on inflammation and autoimmune diseases. However, the therapeutic application of TP is hindered by severe cardiomyocyte toxicity and narrow therapeutic window. We previously identified that the p53 was an indispensable contributor in TP-induced myocardial injury. p53 has an inhibitory effect on IKKß-NF-κB pathway that regulates glucose transporters (GLUT) expression. Based on these evidences, we speculate that p53 mediates TP-disturbed glucose uptake by blocking IKKß-NF-κB signaling. This study focused on the effect of TP on cardiac glucose uptake and the role of p53 in glucose metabolism in cardiomyocytes, and p53 -/- mice. TP treatment depressed glucose consumption and ATP production resulting in myocardial damage. Incubation with ATP (5 mM) remarkably decreased the cellular damage. Immunoblotting and immunofluorescence identified that TP suppressed glucose uptake by restricting IKKß-NF-κB signaling activation, GLUT1 and GLUT4 expression. p53 inhibition alleviated the cell damage and the compromise of glucose uptake. Mechanistically, p53 antagonist PFTα abolished TP-induced the inhibition of IKKß, IκBα phosphorylation, p65 nuclear translocation, and GLUT1, GLUT4 expression. Consistently, in acute heart injury models, p53 deficiency upregulated IKKß-NF-κB activation and GLUT1, GLUT4 protein levels which was also indicated as amelioration of heart histological injury after 1.2 mg kg-1 TP administration. The present findings indicate that TP-induced p53 overactivation suppresses glucose uptake by inhibiting IKKß-NF-κB pathway and downregulating NF-κB-dependent GLUT1 and GLUT4 expression.


Assuntos
Diterpenos/toxicidade , Glucose/metabolismo , Cardiopatias/induzido quimicamente , Quinase I-kappa B/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , NF-kappa B/metabolismo , Fenantrenos/toxicidade , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose/efeitos dos fármacos , Cardiotoxicidade , Linhagem Celular , Metabolismo Energético/efeitos dos fármacos , Compostos de Epóxi/toxicidade , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Cardiopatias/genética , Cardiopatias/metabolismo , Cardiopatias/patologia , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/genética
7.
Cell Mol Biol (Noisy-le-grand) ; 65(7): 55-59, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31880518

RESUMO

To investigate the effect of polydatin on glucose transporter, blood glucose homeostasis and renal injury in streptozotocin (STZ)-induced diabetic rats. The in vitro inhibitory effect of polydatin on sodium-glucose cotransporter-1 (SGLT1) and 2 (SGLT2) was determined using HEK293 cells. The inhibitory effect of polydatin on GLUT1 and GLUT4 was evaluated using 3T3-L1 adipocytes. Streptozotocin-induced diabetic rats were used for this study. Fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), urea nitrogen, serum creatinine and urinary protein were determined using biochemical analyzer. Histopathological examination was performed on renal tissue. Serum levels of interleukin 1ß (IL-1ß), tumor necrosis factor α (TNF-α), monocyte chemoattractant protein 1 (MCP-1) and C-reactive protein (CRP) were also determined. Polydatin significantly inhibited SGLT1/2 and exhibited high selectivity for both GLUT1 and GLUT4. It significantly and dose-dependently decreased hyperglycemia, enhanced urine glucose excretion in the diabetic rats. The polydatin treatment significantly ameliorated symptoms of DN such as polyuria, polydipsia and hyperphagia. The hypoglycemic effect of polydatin was maintained throughout the treatment period. In addition,the levels of IL-1ß, TNF-α, MCP-1 and CRP were significantly reduced in treated group. Treatment with polydatin significantly ameliorated most of the structural and morphological changes induced by STZ. Moreover, the levels of urinary protein, serum creatinine and urea nitrogen were significantly reduced after treatment with polydatin.  As a potential dual inhibitor of SGLT1/2, polydatin has high selectivity for GLUT1 and GLUT4. Its long-term administration delays the development of DN, protects renal function and ameliorates renal tissue injury.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Glucosídeos/uso terapêutico , Hiperglicemia/tratamento farmacológico , Estilbenos/uso terapêutico , Células 3T3-L1 , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Células HEK293 , Humanos , Hiperglicemia/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Camundongos , Transportador 1 de Glucose-Sódio/metabolismo , Transportador 2 de Glucose-Sódio/metabolismo
8.
Parasitol Res ; 118(12): 3429-3441, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31667591

RESUMO

The parasite Cryptosporidium parvum Tyzzer 1912 destroys parts of the intestinal brush border membrane which is important for the uptake of nutrients like glucose. In this study, glucose transport mechanisms of the host cells (IPEC-J2 cells) infected by C. parvum were investigated. The mRNA expression levels of glucose transporters (GLUT) 1 and 2 and Na+-coupled glucose transporter (SGLT) 1 were compared in infected and uninfected cells over an infection time of 24-96 h by RT-qPCR. Furthermore, the protein expression of SGLT 1 and GLUT 2 was quantified in western blot studies. While the protein expression of SGLT 1 was not altered in infected cells, mRNA expression of SGLT 1 and GLUT 1 was significantly increased 24 h p. i. and decreased 96 h p. i. The mRNA expression of GLUT 2 was significantly decreased 24 h, 72 h, and 96 h p. i. and also correlated significantly with the infection dose at 72 h p. i. In contrast to that, the protein expression of GLUT 2 was significantly increased 48 h p. i., associated with a significantly higher intracellular glucose level in infected cells compared with control cells at that time point of infection. This points to an adaptation of the host cells' glucose uptake taking place in the acute phase of the infection. A better understanding of these molecular mechanisms following a C. parvum infection may probably lead to an improvement of therapy strategies in the future.


Assuntos
Criptosporidiose/patologia , Cryptosporidium parvum/metabolismo , Enterócitos/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Transportador 1 de Glucose-Sódio/metabolismo , Animais , Transporte Biológico , Linhagem Celular , Criptosporidiose/parasitologia , Enterócitos/parasitologia , Glucose/metabolismo , Suínos
9.
Int J Mol Sci ; 20(19)2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31597342

RESUMO

An increasing body of evidence indicates that bio-energetic metabolism of T cells can be manipulated to control T cell responses. This potentially finds a field of application in the control of the T cell responses in autoimmune diseases, including in type 1 diabetes (T1D). Of the possible metabolic targets, Glut1 gained considerable interest because of its pivotal role in glucose uptake to fuel glycolysis in activated T cells, and the recent development of a novel class of small molecules that act as selective inhibitor of Glut1. We believe we can foresee a possible application of pharmacological Glut1 blockade approach to control autoreactive T cells that destroy insulin producing beta cells. However, Glut1 is expressed in a broad range of cells in the body and off-target and side effect are possible complications. Moreover, the duration of the treatment and the age of patients are critical aspects that need to be addressed to reduce toxicity. In this paper, we will review recent literature to determine whether it is possible to design a pharmacological Glut1 blocking strategy and how to apply this to autoimmunity in T1D.


Assuntos
Autoimunidade , Transportador de Glucose Tipo 1/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/etiologia , Doenças Autoimunes/metabolismo , Autoimunidade/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Regulação da Expressão Gênica , Transportador de Glucose Tipo 1/antagonistas & inibidores , Transportador de Glucose Tipo 1/química , Transportador de Glucose Tipo 1/genética , Humanos , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Terapia de Alvo Molecular , Transdução de Sinais , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos
10.
Zhongguo Zhong Yao Za Zhi ; 44(17): 3786-3791, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31602954

RESUMO

It is reported that energy metabolism is the core feature of tumor cells. This study is aimed to investigate the regulatory effect of two flavonoids( glabridin and quercetin) on energy supply and glycolysis of breast cancer cells,and provide reference for developing some anticancer herbal drugs with the function of regulating tumor energy metabolism. Based on the characteristics of each pathway during energy metabolism,in the present study,the triple negative breast cancer tumor cells( MDA-MB-231) were selected to investigate the effects of glabridin and quercetin on the energy metabolism of breast cancer cells and discuss the possible mechanisms from the following five potential targets: glucose uptake,protein expression of glucose transporter 1( GLUT1),adenosine triphosphate( ATP) level,lactate dehydrogenase( LDH) activity,and lactic acid( LD) concentration. The results showed that both quercetin and glabridin could decrease the glucose uptake capacity of breast cancer cells by down-regulating the protein expression of GLUT1. Quercetin had no significant effect on LDH activity and LD concentration; it did not affect the glycolysis process,but increased the intracellular ATP level. Glabridin decreased the activity of LDH and reduced LD concentration,thereby inhibiting the glycolysis metabolism of breast cancer cells. Therefore,both quercetin and glabridin can regulate the energy metabolism of breast cancer cells and can be used as potential anticancer agents or anti-cancer adjuvants.


Assuntos
Neoplasias da Mama/metabolismo , Metabolismo Energético , Isoflavonas/farmacologia , Fenóis/farmacologia , Quercetina/farmacologia , Linhagem Celular Tumoral , Glucose/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Humanos
11.
Nat Commun ; 10(1): 4320, 2019 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-31541095

RESUMO

OTULIN (OTU Deubiquitinase With Linear Linkage Specificity) specifically hydrolyzes methionine1 (Met1)-linked ubiquitin chains conjugated by LUBAC (linear ubiquitin chain assembly complex). Here we report on the mass spectrometric identification of the OTULIN interactor SNX27 (sorting nexin 27), an adaptor of the endosomal retromer complex responsible for protein recycling to the cell surface. The C-terminal PDZ-binding motif (PDZbm) in OTULIN associates with the cargo-binding site in the PDZ domain of SNX27. By solving the structure of the OTU domain in complex with the PDZ domain, we demonstrate that a second interface contributes to the selective, high affinity interaction of OTULIN and SNX27. SNX27 does not affect OTULIN catalytic activity, OTULIN-LUBAC binding or Met1-linked ubiquitin chain homeostasis. However, via association, OTULIN antagonizes SNX27-dependent cargo loading, binding of SNX27 to the VPS26A-retromer subunit and endosome-to-plasma membrane trafficking. Thus, we define an additional, non-catalytic function of OTULIN in the regulation of SNX27-retromer assembly and recycling to the cell surface.


Assuntos
Endopeptidases/metabolismo , Endossomos/metabolismo , Nexinas de Classificação/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Endopeptidases/química , Técnicas de Inativação de Genes , Transportador de Glucose Tipo 1/metabolismo , Células HEK293 , Humanos , Modelos Moleculares , Domínios PDZ , Ligação Proteica , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Transporte Proteico , Nexinas de Classificação/química , Nexinas de Classificação/genética , Ubiquitinação , Proteínas de Transporte Vesicular/metabolismo
12.
Pharm Res ; 36(10): 141, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31367840

RESUMO

PURPOSE: The purpose of the present study was to investigate changes of blood-brain barrier (BBB) and brain parenchymal protein expression due to type II diabetes mellitus (T2DM) induced by a high-fat diet (HFD) by using SWATH-based quantitative proteomics. METHODS: Mice were fed a HFD for 2 or 10 weeks, and then SWATH-based quantitative proteomic analysis, western blot analysis, immunohistochemistry and functional transport studies were performed. RESULTS: In brain capillaries, expression levels of BBB transporters (Glut1, P-glycoprotein) and tight-junction proteins (claudin-5, occludin) were significantly reduced in HFD mice at 2 weeks, but recovered to the levels in the normal diet (ND) group at 10 weeks. P-glycoprotein function at the BBB was reduced at 2 weeks. In the cerebral cortex and hippocampus, neurofilament, which is important for neuronal function, was decreased in HFD mice at 2 weeks, but recovered at 10 weeks. CONCLUSION: Our results suggest that changes in the status of insulin resistance influence expression of BBB transporters, which in turn may alter the expression of cognitive function-related proteins.


Assuntos
Encéfalo/metabolismo , Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina , Insulina/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/irrigação sanguínea , Capilares/metabolismo , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Filamentos Intermediários/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Proteômica , Proteínas de Junções Íntimas/metabolismo
13.
Pharm Res ; 36(10): 140, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31367876

RESUMO

PURPOSE: In order to overcome the obstacles and side effects of classical chemotherapy, numerous studies have been performed to develop the treatment based on targeted transport of active compounds directly to the site of action. Since tumor cells are featured with intensified glucose metabolism, we set out to develop innovative, glucose-modified PAMAM dendrimer for the delivery of doxorubicin to breast cancer cells. METHODS: PAMAM-dox-glc conjugate was synthesized and characterized by 1H NMR, FT-IR, size and zeta potential measurements. The drug release rate from conjugate was evaluated by dialysis under different pH conditions. The expression level of GLUT family receptors in cells cultured in full and glucose-deprived medium was evaluated by quantitative real-time RT-PCR and flow cytometry. The cytotoxicity of conjugate in presence or absence of GLUT1 inhibitors was determined by MTT assay. RESULTS: We showed that PAMAM-dox-glc conjugate exhibits pH-dependent drug release and increased cytotoxic activity compared to free drug in cells cultured in medium without glucose. Further, we proved that these cells overexpress transporters of GLUT family. The toxic effect of conjugate was eliminated by the application of specific GLUT1 inhibitors. CONCLUSION: Our findings revealed that the glucose moiety plays a crucial role in the recognition of cells with high expression of GLUT receptors. By selectively blocking GLUT1 transporter we showed its importance for the cytotoxic activity of PAMAM-dox-glc conjugate. These results suggest that PAMAM-glucose formulations may constitute an efficient platform for the specific delivery of anticancer drugs to tumor cells overexpressing transporters of GLUT family.


Assuntos
Antineoplásicos/farmacologia , Dendrímeros/química , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Transportador de Glucose Tipo 1/metabolismo , Glucose/efeitos adversos , Antineoplásicos/administração & dosagem , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Liberação Controlada de Fármacos , Regulação da Expressão Gênica , Glucose/química , Humanos , Concentração de Íons de Hidrogênio , Células MCF-7 , Tamanho da Partícula
14.
Eur J Med Chem ; 182: 111612, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31421631

RESUMO

Sugar, as a carrier of human energy and an important bioinformatics molecule, plays a vital role in many important physiological processes, and can control the transmission of bioinformatics by specific recognition with biological molecules such as proteins. Herein, the mechanism of glycosylation-targeted drug delivery was described, various glycosylation methods were summarized, and the applications of glycosylation-targeted drug delivery in liver targeting, brain targeting and lung targeting were discussed. At the same time, the problems of glycosylation targeted drug delivery were suggested, and the application prospects of glycosylation targeting drug delivery were expected.


Assuntos
Sistemas de Liberação de Medicamentos , Transportador de Glucose Tipo 1/antagonistas & inibidores , Receptores Mitogênicos/antagonistas & inibidores , Animais , Transportador de Glucose Tipo 1/metabolismo , Glicosilação , Humanos , Receptores Mitogênicos/metabolismo
15.
Mol Cell ; 76(1): 148-162.e7, 2019 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-31447391

RESUMO

The rapid proliferation of cancer cells and dysregulated vasculature within the tumor leads to limited nutrient accessibility. Cancer cells often rewire their metabolic pathways for adaption to nutrient stress, and the underlying mechanism remains largely unknown. Glutamate dehydrogenase 1 (GDH1) is a key enzyme in glutaminolysis that converts glutamate to α-ketoglutarate (α-KG). Here, we show that, under low glucose, GDH1 is phosphorylated at serine (S) 384 and interacts with RelA and IKKß. GDH1-produced α-KG directly binds to and activates IKKß and nuclear factor κB (NF-κB) signaling, which promotes glucose uptake and tumor cell survival by upregulating GLUT1, thereby accelerating gliomagenesis. In addition, GDH1 S384 phosphorylation correlates with the malignancy and prognosis of human glioblastoma. Our finding reveals a unique role of α-KG to directly regulate signal pathway, uncovers a distinct mechanism of metabolite-mediated NF-κB activation, and also establishes the critical role of α-KG-activated NF-κB in brain tumor development.


Assuntos
Neoplasias Encefálicas/metabolismo , Proliferação de Células , Metabolismo Energético , Glioblastoma/metabolismo , Glucose/metabolismo , Glutamato Desidrogenase/metabolismo , Ácidos Cetoglutáricos/metabolismo , NF-kappa B/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular , Criança , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/patologia , Glucose/deficiência , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Glutamato Desidrogenase/genética , Células HEK293 , Humanos , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , NF-kappa B/genética , Gradação de Tumores , Fosforilação , Transdução de Sinais , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Adulto Jovem
17.
Gen Comp Endocrinol ; 283: 113232, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31356813

RESUMO

Avian glucose transporters (GLUT) responsible for insulin-responsive glucose uptake into adipocytes remain poorly characterized. We aimed to identify the insulin-responsive GLUT using primary culture of chicken adipocytes. Acute stimulation with 1 µM insulin for 20 min increased 2-deoxyglucose uptake, AKT protein phosphorylation, and GLUT1 protein levels on the plasma membrane of the chicken adipocytes, whereas pretreatment with 10 µM triciribine, an AKT inhibitor, canceled these effects. Furthermore, the insulin stimulation did not affect GLUT12 protein levels on the plasma membrane of the chicken adipocytes. Our results suggest that GLUT1 is an insulin-responsive GLUT in chicken adipocytes.


Assuntos
Adipócitos/metabolismo , Membrana Celular/metabolismo , Galinhas/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Glucose/metabolismo , Insulina/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Adipócitos/efeitos dos fármacos , Animais , Transporte Biológico/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Desoxiglucose/metabolismo , Masculino , Fosforilação/efeitos dos fármacos
18.
Scand J Immunol ; 90(3): e12802, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31269269

RESUMO

Glucose and nutrient uptake is essential in supporting T cell activation and is increased upon CD3/CD28 stimulation. As T cells from pleural effusions secondary to lung cancer show impaired function, we hypothesized that these cells might have altered expression of nutrient transporters. Here, we analysed by flow cytometry the expression of the transferrin receptor CD71, amino acid transporter CD98 and glucose transporter Glut1 and glucose uptake in pleural effusion-derived T cells from lung cancer patients, after stimulation via CD3/CD28 under normoxia or hypoxia (2% O2 ). We compared the response of T cells from pleural effusions secondary to lung cancer with that of T cells from nonmalignant effusions. In memory T cells from both groups, anti-CD3/CD28-stimulation under normoxia upregulated CD98 and CD71 expression (measured as median fluorescence intensity, MFI) in comparison with anti-CD3-stimulation. Costimulation under hypoxia tended to increase CD98 expression compared to CD3-stimulation in memory T cells from both groups. Remarkably, in the cancer group, memory T cells stimulated via CD3/CD28 under hypoxia failed to increase CD71 and Glut1 expression levels compared to the cells receiving anti-CD3 stimulation, a phenomenon that contrasted with the behaviour of memory T cells from nonmalignant effusions. Consequently, glucose uptake by memory T cells from the cancer group was not increased after CD3/CD28 stimulation under hypoxia, implying that their glycolytic metabolism is defective. As this process is required for inducing an antitumoural response, our study suggests that memory T cells are rendered dysfunctional and are unable to eliminate lung tumour cells.


Assuntos
Antígenos CD28/metabolismo , Complexo CD3/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Glucose/metabolismo , Memória Imunológica/imunologia , Neoplasias Pulmonares/metabolismo , Derrame Pleural/metabolismo , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Neoplasias Pulmonares/imunologia , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Derrame Pleural/imunologia , Linfócitos T/metabolismo
19.
Int J Mol Sci ; 20(13)2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31324056

RESUMO

An important hallmark in cancer cells is the increase in glucose uptake. GLUT1 is an important target in cancer treatment because cancer cells upregulate GLUT1, a membrane protein that facilitates the basal uptake of glucose in most cell types, to ensure the flux of sugar into metabolic pathways. The dysregulation of GLUT1 is associated with numerous disorders, including cancer and metabolic diseases. There are natural products emerging as a source for inhibitors of glucose uptake, and resveratrol is a molecule of natural origin with many properties that acts as antioxidant and antiproliferative in malignant cells. In the present review, we discuss how GLUT1 is involved in the general scheme of cancer cell metabolism, the mechanism of glucose transport, and the importance of GLUT1 structure to understand the inhibition process. Then, we review the current state-of-the-art of resveratrol and other natural products as GLUT1 inhibitors, focusing on those directed at treating different types of cancer. Targeting GLUT1 activity is a promising strategy for the development of drugs aimed at treating neoplastic growth.


Assuntos
Transportador de Glucose Tipo 1/metabolismo , Glucose/metabolismo , Neoplasias/metabolismo , Resveratrol/farmacologia , Animais , Humanos
20.
Elife ; 82019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-31169500

RESUMO

GPIHBP1, a GPI-anchored protein of capillary endothelial cells, binds lipoprotein lipase (LPL) within the subendothelial spaces and shuttles it to the capillary lumen. GPIHBP1-bound LPL is essential for the margination of triglyceride-rich lipoproteins (TRLs) along capillaries, allowing the lipolytic processing of TRLs to proceed. In peripheral tissues, the intravascular processing of TRLs by the GPIHBP1-LPL complex is crucial for the generation of lipid nutrients for adjacent parenchymal cells. GPIHBP1 is absent from the capillaries of the brain, which uses glucose for fuel; however, GPIHBP1 is expressed in the capillaries of mouse and human gliomas. Importantly, the GPIHBP1 in glioma capillaries captures locally produced LPL. We use NanoSIMS imaging to show that TRLs marginate along glioma capillaries and that there is uptake of TRL-derived lipid nutrients by surrounding glioma cells. Thus, GPIHBP1 expression in gliomas facilitates TRL processing and provides a source of lipid nutrients for glioma cells.


Assuntos
Glioma/metabolismo , Lipoproteínas/metabolismo , Receptores de Lipoproteínas/metabolismo , Animais , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Capilares/metabolismo , Isótopos de Carbono/metabolismo , Células Endoteliais/metabolismo , Ácidos Graxos/metabolismo , Glioma/irrigação sanguínea , Glioma/patologia , Glioma/ultraestrutura , Glucose/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Humanos , Lipase Lipoproteica/metabolismo , Camundongos Endogâmicos C57BL , Triglicerídeos/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA