Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 11 de 11
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Clin Invest ; 131(1)2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33393495

RESUMO

Metabolic reprogramming is a common hallmark of cancer, but a large variability in tumor bioenergetics exists between patients. Using high-resolution respirometry on fresh biopsies of human lung adenocarcinoma, we identified 2 subgroups reflected in the histologically normal, paired, cancer-adjacent tissue: high (OX+) mitochondrial respiration and low (OX-) mitochondrial respiration. The OX+ tumors poorly incorporated [18F]fluorodeoxy-glucose and showed increased expression of the mitochondrial trifunctional fatty acid oxidation enzyme (MTP; HADHA) compared with the paired adjacent tissue. Genetic inhibition of MTP altered OX+ tumor growth in vivo. Trimetazidine, an approved drug inhibitor of MTP used in cardiology, also reduced tumor growth and induced disruption of the physical interaction between the MTP and respiratory chain complex I, leading to a cellular redox and energy crisis. MTP expression in tumors was assessed using histology scoring methods and varied in negative correlation with [18F]fluorodeoxy-glucose incorporation. These findings provide proof-of-concept data for preclinical, precision, bioenergetic medicine in oxidative lung carcinomas.


Assuntos
Sistemas de Liberação de Medicamentos , Neoplasias Pulmonares/enzimologia , Subunidade alfa da Proteína Mitocondrial Trifuncional , Proteínas de Neoplasias , Trimetazidina/farmacologia , Linhagem Celular Tumoral , Complexo I de Transporte de Elétrons/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Subunidade alfa da Proteína Mitocondrial Trifuncional/antagonistas & inibidores , Subunidade alfa da Proteína Mitocondrial Trifuncional/biossíntese , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/biossíntese , Oxirredução
3.
Biochim Biophys Acta Mol Basis Dis ; 1865(9): 2180-2188, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31034992

RESUMO

Tumor microenvironment has a high concentration of inorganic phosphate (Pi), which is actually a marker for tumor progression. Regarding Pi another class of transporter has been recently studied, an H+-dependent Pi transporter, that is stimulated at acidic pH in Caco2BBE human intestinal cells. In this study, we characterized the H+-dependent Pi transport in breast cancer cell (MDA-MB-231) and around the cancer tissue. MDA-MB-231 cell line presented higher levels of H+-dependent Pi transport as compared to other breast cell lines, such as MCF-10A, MCF-7 and T47-D. The Pi transport was linear as a function of time and exhibited a Michaelis-Menten kinetic of Km = 1.387 ±â€¯0.1674 mM Pi and Vmax = 198.6 ±â€¯10.23 Pi × h-1 × mg protein-1 hence reflecting a low affinity Pi transport. H+-dependent Pi uptake was higher at acidic pH. FCCP, Bafilomycin A1 and SCH28080, which deregulate the intracellular levels of protons, inhibited the H+-dependent Pi transport. No effect on pHi was observed in the absence of inorganic phosphate. PAA, an H+-dependent Pi transport inhibitor, reduced the Pi transport activity, cell proliferation, adhesion, and migration. Arsenate, a structural analog of Pi, inhibited the Pi transport. At high Pi conditions, the H+-dependent Pi transport was five-fold higher than the Na+-dependent Pi transport, thus reflecting a low affinity Pi transport. The occurrence of an H+-dependent Pi transporter in tumor cells may endow them with an alternative path for Pi uptake in situations in which Na+-dependent Pi transport is saturated within the tumor microenvironment, thus regulating the energetically expensive tumor processes.


Assuntos
Proteínas de Transporte de Fosfato/metabolismo , Fosfatos/metabolismo , Microambiente Tumoral , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Caderinas/genética , Caderinas/metabolismo , Adesão Celular , Linhagem Celular , Proliferação de Células , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Transporte de Íons/efeitos dos fármacos , Cinética , Ácido Fosfonoacéticos/farmacologia , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIb/genética , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIb/metabolismo , Regulação para Cima/efeitos dos fármacos
4.
Front Oncol ; 9: 1430, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31921682

RESUMO

Tumor cells exhibit rewired metabolism. We carried out comparative analyses attempting to investigate whether metabolic reprograming could be measured by isothermal microcalorimetry. Intact metastatic cell lines of tongue cell carcinoma, human and murine melanoma, lung, and breast tumors consistently released more heat than non-metastatic cells or cells displaying lower metastatic potential. In tongue squamous carcinoma cells mitochondrial enriched extract reproduced the heat release pattern of intact cells. Cytochalasin D, an actin filament inhibitor, and suppression of metastasis marker Melanoma associated gene 10 (MAGEA10) decreased heat release. Uncoupling protein 2 was highly expressed in metastatic cells, but not in non-metastatic cells. Carnitine palmitoyl transferase-1 inhibitor, Etomoxir strongly inhibited heat release by metastatic cells, thus linking lipid metabolism to thermogenesis. We propose that heat release may be a quantifiable trait of the metastatic process.

5.
Front Oncol ; 8: 441, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30460192

RESUMO

[This corrects the article DOI: 10.3389/fonc.2018.00090.].

6.
Front Oncol ; 8: 90, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29675398

RESUMO

Cancer outcome has improved since introduction of target therapy. However, treatment success is still impaired by the same drug resistance mechanism of classical chemotherapy, known as multidrug resistance (MDR) phenotype. This phenotype promotes resistance to drugs with different structures and mechanism of action. Recent reports have shown that resistance acquisition is coupled to metabolic reprogramming. High-gene expression, increase of active transport, and conservation of redox status are one of the few examples that increase energy and substrate demands. It is not clear if the role of this metabolic shift in the MDR phenotype is related to its maintenance or to its induction. Apart from the nature of this relation, the metabolism may represent a new target to avoid or to block the mechanism that has been impairing treatment success. In this mini-review, we discuss the relation between metabolism and MDR resistance focusing on the multiple non-metabolic functions that enzymes of the glycolytic pathway are known to display, with emphasis with the diverse activities of glyceraldehyde-3-phosphate dehydrogenase.

7.
PLoS One ; 13(2): e0191270, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29415049

RESUMO

BACKGROUND: Recent studies demonstrate that interstitial inorganic phosphate is significantly elevated in the breast cancer microenvironment as compared to normal tissue. In addition it has been shown that breast cancer cells express high levels of the NaPi-IIb carrier (SLC34A2), suggesting that this carrier may play a role in breast cancer progression. However, the biochemical behavior of inorganic phosphate (Pi) transporter in this cancer type remains elusive. METHODS: In this work, we characterize the kinetic parameters of Pi transport in the aggressive human breast cancer cell line, MDA-MB-231, and correlated Pi transport with cell migration and adhesion. RESULTS: We determined the influence of sodium concentration, pH, metabolic inhibitors, as well as the affinity for inorganic phosphate in Pi transport. We observed that the inorganic phosphate is dependent on sodium transport (K0,5 value = 21.98 mM for NaCl). Furthermore, the transport is modulated by different pH values and increasing concentrations of Pi, following the Michaelis-Menten kinetics (K0,5 = 0.08 mM Pi). PFA, monensin, furosemide and ouabain inhibited Pi transport, cell migration and adhesion. CONCLUSIONS: Taken together, these results showed that the uptake of Pi in MDA-MB-231 cells is modulated by sodium and by regulatory mechanisms of intracellular sodium gradient. General Significance: Pi transport might be regarded as a potential target for therapy against tumor progression.


Assuntos
Compostos Inorgânicos/metabolismo , Fosfatos/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Transporte Biológico , Adesão Celular , Linhagem Celular Tumoral , Movimento Celular , Feminino , Humanos , Cinética , Neoplasias de Mama Triplo Negativas/patologia
8.
J Cell Biochem ; 116(5): 797-808, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25510910

RESUMO

Tumor cells display different bioenergetic profiles when compared to normal cells. In the present work we showed metabolic reprogramming by means of inhibitors of histone deacetylase (HDACis), sodium butyrate and trichostatin A in breast cancer cells representing different stages of aggressiveness and metabolic profile. When testing the effect of NaB and TSA on viability of cells, it was shown that non-tumorigenic MCF-10A cells were less affected by increasing doses of the drugs than the tumorigenic, hormone dependent, tightly cohesive MCF-7, T-47D and the highly metastatic triple-negative MDA-MB 231 cells. T-47D cells were the most sensitive to treatment with both, NaB and TSA. Experiments measuring anchorage- independent growth of tumor cells showed that MCF-7, T-47D, and MDA-MB-231 cells were equally sensitive to the treatment with NaB. The NaB induced an attenuation of glycolysis, reflected by a decrease in lactate release in MCF-7 and T47D lines. Pyruvate kinase activity was significantly enhanced by NaB in MDA-MB-231 cells only. In contrast, the inhibitor enhanced lactate dehydrogenase activity specifically in T-47 D cells. Glucose-6-phosphate dehydrogenase activity was shown to be differentially modulated by NaB in the cell lines investigated: the enzyme was inhibited in MCF-7 cells, whereas in T-47D and MDA-MB-231 cells, G6PDH was activated. NaB and TSA were able to significantly increase the oxygen consumption by MDA-MB-231 and T-47D cells. Collectively the results show that epigenetic changes associated to acetylation of proteins in general affect the energy metabolism in all cancer cell lines and that mitochondria may occupy a central role in metastasis.


Assuntos
Neoplasias da Mama/metabolismo , Ácido Butírico/metabolismo , Metabolismo Energético , Inibidores de Histona Desacetilases/metabolismo , Ácidos Hidroxâmicos/metabolismo , Linhagem Celular Tumoral , Glicólise , Humanos , Redes e Vias Metabólicas , Oxirredução
9.
Int J Biochem Cell Biol ; 51: 53-7, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24661997

RESUMO

Since the nineteenth century the importance of mitochondria in cellular physiology has been growing steadily. Not only the organelle harbors the main systems for ATP generation, but also buffers the redox potential in the cytosol and is one of the protagonists of the intrinsic pathway for apoptosis. In tumor cells, mitochondria went from being dysfunctional compartments to playing a supportive or perhaps even a triggering part in metastasis. This "Organelle In Focus" article discusses the classical metabolic events that occur in mitochondria and why these pathways could be essential for the onset of the malignant phenotype. Finally, we propose that the oxidative metabolism of tumor cells in conjunction with the inactivation of anoikis may have been coopted through a non-adaptive evolutionary process.


Assuntos
Mitocôndrias/metabolismo , Neoplasias/patologia , Animais , Humanos , Metástase Neoplásica , Neoplasias/metabolismo , Microambiente Tumoral
10.
Biosci Rep ; 33(6)2013 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-24079832

RESUMO

Tumour cells thrive in environments that would be hostile to their normal cell counterparts. Survival depends on the selection of cell lines that harbour modifications of both, gene regulation that shifts the balance between the cell cycle and apoptosis and those that involve the plasticity of the metabolic machinery. With regards to metabolism, the selected phenotypes usually display enhanced anaerobic glycolysis even in the presence of oxygen, the so-called Warburg effect, and anabolic pathways that provide precursors for the synthesis of lipids, proteins and DNA. The review will discuss the original ideas of Otto Warburg and how they initially led to the notion that mitochondria of tumour cells were dysfunctional. Data will be presented to show that not only the organelles are viable and respiring, but that they are key players in tumorigenesis and metastasis. Likewise, interconnecting pathways that stand out in the tumour phenotype and that require intact mitochondria such as glutaminolysis will be addressed. Furthermore, comments will be made as to how the peculiarities of the biochemistry of tumour cells renders them amenable to new forms of treatment by highlighting possible targets for inhibitors. In this respect, a case study describing the effect of a metabolite analogue, the alkylating agent 3BP (3-bromopyruvate), on glycolytic enzyme targets will be presented.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Neoplasias/metabolismo , Animais , Antineoplásicos/farmacologia , Glutamina/metabolismo , Glicólise , Humanos , Mitocôndrias/metabolismo , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia
11.
PLoS One ; 6(7): e22264, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21789245

RESUMO

BACKGROUND: Tumor cells are characterized by accelerated growth usually accompanied by up-regulated pathways that ultimately increase the rate of ATP production. These cells can suffer metabolic reprogramming, resulting in distinct bioenergetic phenotypes, generally enhancing glycolysis channeled to lactate production. In the present work we showed metabolic reprogramming by means of inhibitors of histone deacetylase (HDACis), sodium butyrate and trichostatin. This treatment was able to shift energy metabolism by activating mitochondrial systems such as the respiratory chain and oxidative phosphorylation that were largely repressed in the untreated controls. METHODOLOGY/PRINCIPAL FINDINGS: Various cellular and biochemical parameters were evaluated in lung cancer H460 cells treated with the histone deacetylase inhibitors (HDACis), sodium butyrate (NaB) and trichostatin A (TSA). NaB and TSA reduced glycolytic flux, assayed by lactate release by H460 cells in a concentration dependent manner. NaB inhibited the expression of glucose transporter type 1 (GLUT 1), but substantially increased mitochondria bound hexokinase (HK) activity. NaB induced increase in HK activity was associated to isoform HK I and was accompanied by 1.5 fold increase in HK I mRNA expression and cognate protein biosynthesis. Lactate dehydrogenase (LDH) and pyruvate kinase (PYK) activities were unchanged by HDACis suggesting that the increase in the HK activity was not coupled to glycolytic flux. High resolution respirometry of H460 cells revealed NaB-dependent increased rates of oxygen consumption coupled to ATP synthesis. Metabolomic analysis showed that NaB altered the glycolytic metabolite profile of intact H460 cells. Concomitantly we detected an activation of the pentose phosphate pathway (PPP). The high O(2) consumption in NaB-treated cells was shown to be unrelated to mitochondrial biogenesis since citrate synthase (CS) activity and the amount of mitochondrial DNA remained unchanged. CONCLUSION: NaB and TSA induced an increase in mitochondrial function and oxidative metabolism in H460 lung tumor cells concomitant with a less proliferative cellular phenotype.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Neoplasias Pulmonares/metabolismo , Butiratos/farmacologia , Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Respiração Celular/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Glucose 1-Desidrogenase/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Transportador de Glucose Tipo 3/metabolismo , Glicólise/efeitos dos fármacos , Hexoquinase/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacologia , L-Lactato Desidrogenase/metabolismo , Lactatos/metabolismo , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Ligação Proteica/efeitos dos fármacos , Piruvato Quinase/metabolismo , Succinato Desidrogenase/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...