293 results on '"MCT1"'
Search Results
252. Temporal changes in mRNA expression of the brain nutrient transporters in the lithium-pilocarpine model of epilepsy in the immature and adult rat
- Author
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Luc Pellerin, Susan J. Vannucci, Astrid Nehlig, Ian A. Simpson, Karin Pierre, and Claire Leroy
- Subjects
Blood Glucose ,Male ,Monocarboxylic Acid Transporters ,medicine.medical_specialty ,Aging ,Lithium–pilocarpine ,Status epilepticus ,In situ hybridization ,MCT1 ,MCT2 ,Muscarinic Agonists ,Article ,lcsh:RC321-571 ,Rats, Sprague-Dawley ,Epilepsy ,Status Epilepticus ,Antimanic Agents ,Internal medicine ,Piriform cortex ,medicine ,Animals ,RNA, Messenger ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Glucose Transporter Type 1 ,biology ,Glucose Transporter Type 3 ,Symporters ,Aging/genetics ,Aging/physiology ,Animals, Newborn ,Antimanic Agents/toxicity ,Blood Glucose/metabolism ,Disease Models, Animal ,Epilepsy, Temporal Lobe/genetics ,Epilepsy, Temporal Lobe/metabolism ,Female ,Glucose Transporter Type 1/genetics ,Glucose Transporter Type 3/genetics ,Lithium Compounds/toxicity ,Monocarboxylic Acid Transporters/genetics ,Muscarinic Agonists/toxicity ,Pilocarpine/toxicity ,RNA, Messenger/biosynthesis ,Rats ,Status Epilepticus/genetics ,Status Epilepticus/metabolism ,Symporters/genetics ,Pilocarpine ,medicine.disease ,Endocrinology ,Neurology ,Epilepsy, Temporal Lobe ,biology.protein ,Lithium Compounds ,GLUT1 ,medicine.symptom ,GLUT3 ,medicine.drug - Abstract
The lithium–pilocarpine model mimics most features of human temporal lobe epilepsy. Following our prior studies of cerebral metabolic changes, here we explored the expression of transporters for glucose (GLUT1 and GLUT3) and monocarboxylates (MCT1 and MCT2) during and after status epilepticus (SE) induced by lithium–pilocarpine in PN10, PN21, and adult rats. In situ hybridization was used to study the expression of transporter mRNAs during the acute phase (1, 4, 12 and 24 h of SE), the latent phase, and the early and late chronic phases. During SE, GLUT1 expression was increased throughout the brain between 1 and 12 h of SE, more strongly in adult rats; GLUT3 increased only transiently, at 1 and 4 h of SE and mainly in PN10 rats; MCT1 was increased at all ages but 5-10-fold more in adult than in immature rats; MCT2 expression increased mainly in adult rats. At all ages, MCT1 and MCT2 up-regulation was limited to the circuit of seizures while GLUT1 and GLUT3 changes were more widespread. During the latent and chronic phases, the expression of nutrient transporters was normal in PN10 rats. In PN21 rats, GLUT1 was up-regulated in all brain regions. In contrast, in adult rats GLUT1 expression was down-regulated in the piriform cortex, hilus and CA1 as a result of extensive neuronal death. The changes in nutrient transporter expression reported here further support previous findings in other experimental models demonstrating rapid transcriptional responses to marked changes in cerebral energetic/glucose demand.
- Published
- 2010
253. MCT1-, MCT4- ja CD147-proteiinit kehittyvässä kilin pötsissä
- Author
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Helsingin yliopisto, Eläinlääketieteellinen tiedekunta, Tiihonen, Heidi, Helsingin yliopisto, Eläinlääketieteellinen tiedekunta, and Tiihonen, Heidi
- Abstract
Nuoren märehtijän alkaessa syödä kiinteää ravintoa, etumahojen suhteellinen osuus mahoista kasvaa ja niiden seinämän epiteeli alkaa kehittyä mahdollistaakseen ravintoaineiden tehokkaan imeytymisen. Märehtijöillä rehun hiilihydraatit hajoavat pötsissä haihtuviksi rasvahapoiksi, ja monokarboksylaattikuljettajien uskotaan avustavan haihtuvien rasvahappojen imeytymisessä pötsin seinämän läpi. Pötsin seinämässä on todettu olevan ainakin MCT1- ja MCT4 –isoformeja. Nämä tarvitsevat toimiakseen CD147 -proteiinin (myös OX-47, EMMPRIN, HT7 ja basigin), joka on on glykosyloitu integraalinen membraaniproteiini. Tämän tutkimuksen tarkoituksena oli selvittää MCT1-, MCT4- ja CD147 –proteiinien muutoksia pötsin toiminnan kehittymisen aikana. Toisena tavoitteena oli selvittää, voidaanko näytteenä käyttää solukalvojen sijasta pötsin seinämästä tehtyä homogenaattia. Tutkimuksessa käytettiin eri ikäisinä lopetetuista kileistä kerättyjä näytteitä. Kilejä oli yhteensä 31, joista 7 oli 3-21 tunnin ikäisiä, 7 viikon ikäisiä, 7 kahden viikon ikäisiä, 1 kolmen viikon ikäinen, 2 neljän viikon ikäistä, sekä 7 kahdeksan viikon ikäistä. Pötsin seinämästä otettiin näyte, josta valmistettiin homogenaatti ja eristettiin solukalvot eli membraanit. Pötsinäytteistä löydettiin MCT1- ja CD147 –proteiineja, mutta MCT4- isoformia ei ollut havaittavissa. Membraaninäytteissä havaittiin MCT1 -isoformin pitoisuuksien kasvavan iän mukana, paitsi kahdeksan viikon ikäisillä kileillä, joilla MCT1 –isoformin määrät vähenivät merkitsevästi. CD147 –proteiinia oli havaittavissa jo vastasyntyneiden kilien pötsinäytteissä. Membraaninäytteissä CD147 -proteiinin määrä kasvoi lineaarisesti iän mukana ja CD147- proteiinin ja MCT1 –isoformin välillä havaittiin tilastollisesti merkitsevä korrelaatio. Homogenaattinäytteissä MCT1 -isoformin määrissä ei havaittu korrelaatiota iän kanssa. MCT1- ja MCT4 -isoformien solukalvolle siirtymisessä avustavan CD147 –proteiinin ei myöskään havaittu korreloivan koe-eläinten iän tai MCT1 -i
- Published
- 2012
254. MCT1 T1470A polymorphism influences adherence to strength training in overweight and obese men following a weight loss program
- Author
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Teresa Amigo, B. Szendrei, J. Butragueño, R. Cupeiro, Rojo-Tirado, Domingo González-Lamuño, and Ana B. Peinado
- Subjects
Gerontology ,medicine.medical_specialty ,Strength training ,business.industry ,Weight loss program ,MCT1 ,Weight Loss Program ,Overweight ,Training adherence ,Polymorphism (computer science) ,Physiology (medical) ,medicine ,Physical therapy ,Orthopedics and Sports Medicine ,Obesity ,medicine.symptom ,business - Published
- 2015
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255. Endogenous Gene and Protein Expression of Drug Transporting Proteins in Cell Lines Routinely used in Drug Discovery Programs
- Author
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Ahlin, Gustav, Hilgendorf, Constanze, Karlsson, Johan, Al-Khalili Szigyarto, Cristina, Uhlén, Mathias, Artursson, Per, Ahlin, Gustav, Hilgendorf, Constanze, Karlsson, Johan, Al-Khalili Szigyarto, Cristina, Uhlén, Mathias, and Artursson, Per
- Abstract
The aim of this study was to investigate the gene and protein expression profiles of important drug transporting proteins in human cell lines commonly used for studies of drug transport mechanisms. Human cell lines used to transiently or stably express single transporters (HeLa, HEK293) and leukaemia cell lines used to study drug resistance by ABC-transporters (HL-60, K562) were investigated, and compared with organotypic cell lines (HepG2, Saos-2, Caco-2 and Caco-2 TC7). For gene expression studies, real-time PCR was used, while monospecific polyclonal antibodies were generated and used to investigate protein expression by immunohistochemistry. Thirty-six transporters were studied for gene expression and nine for protein expression. The antibodies were validated using expression patterns in human tissues. Finally, the function of one ubiquitously expressed transporter, MCT1; SLC16A1 was investigated using 14C-lactic acid as a substrate. In general, the adherent cell lines (HeLa, HEK293) displayed low transporter expression and the expression patterns were barely affected by transfection. The leukaemia cell lines (K562, HL-60) and Saos-2 also had low endogenous transporter expression, while the organotypic cell lines (HepG2 and Caco-2) showed higher expression of some transporters. Comparison of gene and protein expression profiles gave poor correlations, but better agreement was obtained for antibodies with a good validation score, indicating that antibody quality was a significant variable. Importantly, the monocarboxylic acid transporting protein MCT1 was significantly expressed in all, and functional in most of the cell lines, indicating that MCT1 may be a confounding factor when the transport of small anionic drugs is investigated.
- Published
- 2009
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256. Futile cycling of lactate through the plasma membrane of C6 glioma cells as detected by (13C, 2H) NMR
- Author
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Rodrigues, Tiago B., Gray, Heather L., Benito, Marina, Garrido, Susana, Sierra, Alejandra, Geraldes, Carlos F. G. C., Ballesteros, Paloma, Cerdán, Sebastián, Fundação para a Ciência e a Tecnologia (Portugal), Ministério da Educação e Ciência (Portugal), Instituto de Salud Carlos III, Ministerio de Educación y Ciencia (España), Comunidad de Madrid, Consejo Superior de Investigaciones Científicas (España), Universidad Nacional de Educación a Distancia (España), and Arizona State University
- Subjects
13C NMR ,C6 cells ,Monocarboxylate transporter ,MCT1 ,lactate recycling - Abstract
We report a novel (13C, 2H) nuclear magnetic resonance (NMR) procedure to investigate lactate recycling through the monocarboxylate transporter of the plasma membrane of cells in culture. C6 glioma cells were incubated with [3-13C]lactate in Krebs-Henseleit Buffer containing 50% 2H2O (vol/vol) for up to 30 hr. 13C NMR analysis of aliquots progressively taken from the medium, showed: (1) a linearly decreasing singlet at ∼20.85 parts per million (ppm; −0.119 μmol/mg protein/hr) derived from the methyl carbon of [3-13C]lactate; and (2) an exponentially increasing shifted singlet at ∼20.74 ppm (0.227 μmol/ mg protein/hr) from the methyl carbon of [3-13C, 2-2H]lactate. The shifted singlet appears because during its transit through the cytosol, [3-13C]lactate generates [3-13C, 2-2H]lactate in the lactate dehydrogenase (LDH) equilibrium, which may return to the incubation medium through the reversible monocarboxylate carrier. The methyl group of [3-13C, 2-2H]lactate is shifted −0.11 ppm with respect to that of [3-13C]lactate, making it possible to distinguish between both molecules by 13C NMR. During incubations with 2.5 mM [1-13C]glucose and 3.98 mM [U-13C3]lactate or with 2.5 mM [1-13C]glucose and 3.93 mM [2-13C]pyruvate, C2-deuterated lactate was produced only from [1-13C]glucose or [U-13C3]lactate, revealing that this deuteration process is redox sensitive. When [1-13C]glucose and [U-13C3]lactate were used as substrates, no significant [3-13C]lactate production from [1-13C]glucose was detected, suggesting that glycolytic lactate production may be stopped under the high lactate concentrations prevailing under mild hypoxic or ischemic episodes or during cerebral activation., This work was supported by the Spanish Ministry of Education and Science (SAF 2001-2245 to S.C.), Institute of Health Carlos III (FISss C03/08, G03/155 and C03/10 to S.C.), and the Community of Madrid (Strategic Group Grant 2000-3 to P.B.). T.B. Rodrigues was supported by fellowship from Fundaçâo para a Ciência e Tecnologia/ Ministério da Ciência e Ensino Superior-Portugal (SFRH/BD/5407/2001). M. Benito and A. Sierra were predoctoral fellows of CSIC and UNED, respectively. H.L. Gray had a fellowship from the Howard Hughes Bravo Program of the University of Arizona.
- Published
- 2005
257. Dual Inhibition of the Lactate Transporters MCT1 and MCT4 Is Synthetic Lethal with Metformin due to NAD+ Depletion in Cancer Cells.
- Author
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Benjamin D, Robay D, Hindupur SK, Pohlmann J, Colombi M, El-Shemerly MY, Maira SM, Moroni C, Lane HA, and Hall MN
- Subjects
- Acids metabolism, Animals, Cell Line, Tumor, Energy Metabolism drug effects, Humans, Intracellular Space metabolism, Male, Mice, Inbred C57BL, Monocarboxylic Acid Transporters metabolism, Muscle Proteins metabolism, Reserpine analogs & derivatives, Reserpine pharmacology, Symporters metabolism, Lactic Acid metabolism, Metformin pharmacology, Monocarboxylic Acid Transporters antagonists & inhibitors, Muscle Proteins antagonists & inhibitors, NAD metabolism, Neoplasms metabolism, Symporters antagonists & inhibitors, Synthetic Lethal Mutations
- Abstract
Highly glycolytic cancer cells prevent intracellular acidification by excreting the glycolytic end-products lactate and H
+ via the monocarboxylate transporters 1 (MCT1) and 4 (MCT4). We report that syrosingopine, an anti-hypertensive drug, is a dual MCT1 and MCT4 inhibitor (with 60-fold higher potency on MCT4) that prevents lactate and H+ efflux. Syrosingopine elicits synthetic lethality with metformin, an inhibitor of mitochondrial NADH dehydrogenase. NAD+, required for the ATP-generating steps of glycolysis, is regenerated from NADH by mitochondrial NADH dehydrogenase or lactate dehydrogenase. Syrosingopine treatment leads to high intracellular lactate levels and thereby end-product inhibition of lactate dehydrogenase. The loss of NAD+ regeneration capacity due to combined metformin and syrosingopine treatment results in glycolytic blockade, leading to ATP depletion and cell death. Accordingly, ATP levels can be partly restored by exogenously provided NAD+, the NAD precursor nicotinamide mononucleotide (NMN), or vitamin K2. Thus, pharmacological inhibition of MCT1 and MCT4 combined with metformin treatment is a potential cancer therapy., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2018
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258. An overview of MCT1 and MCT4 in GBM: small molecule transporters with large implications.
- Author
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Park SJ, Smith CP, Wilbur RR, Cain CP, Kallu SR, Valasapalli S, Sahoo A, Guda MR, Tsung AJ, and Velpula KK
- Abstract
Monocarboxylate transporters (MCTs) represent a diverse group of transmembrane proteins encoded by the SLC16 gene family found ubiquitously across mammalian species. Two members of this family, MCT1 and MCT4, have been linked to key roles in the metabolic activity of tissues through the proton-coupled transport of monocarboxylates, most notably L-lactate, ketone bodies, and pyruvate. This review aims to provide an overview of MCT1 and MCT4, followed by the implications of their expression in a multitude of cancers and in glioblastoma (GBM) specifically. Further, the possible mechanisms underlying these effects will be discussed. Given the relationships between MCT1 and MCT4 and cancer, they offer a unique opportunity for novel treatment strategies. We aim to explore current therapies focused on MCT1 and MCT4 and propose future studies to better understand their role in GBM to optimize future treatment regimens., Competing Interests: None.
- Published
- 2018
259. Downregulation of monocarboxylate transporter 1 inhibits the invasion and migration through suppression of the PI3K/Akt signaling pathway in human nasopharyngeal carcinoma cells.
- Author
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Zhang P, Ma J, Gao J, Liu F, Sun X, Fang F, Zhao S, and Liu H
- Subjects
- Cadherins metabolism, Carcinoma pathology, Cell Line, Tumor, Cell Movement drug effects, Down-Regulation, Gene Expression Regulation, Neoplastic, Humans, Matrix Metalloproteinase 2 metabolism, Matrix Metalloproteinase 9 metabolism, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, Tissue Inhibitor of Metalloproteinase-1 metabolism, Tissue Inhibitor of Metalloproteinase-2 metabolism, Monocarboxylic Acid Transporters metabolism, Nasopharyngeal Neoplasms pathology, Neoplasm Invasiveness prevention & control, Signal Transduction drug effects, Symporters metabolism
- Abstract
Monocarboxylate transporter 1 (MCT1) has been reported to be correlated wtih decreased survival and advanced stage of progression in a series of human tumor cells and primary cancers. Specifically, MCT1 has been documented to be involved in tumor progression, including invasion and migration. Here, we investigated the mechanism and effect of regulation of MCT1 on invasion and migration of nasopharyngeal carcinoma (NPC) cells. In the study, we firstly demonstrated that the expression of MCT1 in CNE2Z cells was obviously higher than that in HNE1 cells. Downregulation of MCT1 inhibited the invasion and migration in CNE2Z cells, upregulated the expression of E-cadherin, TIMP (tissue inhibitor of metalloproteinase)-2 and TIMP-1, and suppressed the expression of matrix metalloproteinases (MMP)-9 and MMP-2. Correspondingly, upregulation of MCT1 enhanced the invasive and migratory potential in HNE1 cells, increased the expression of MMP-9 and MMP-2, and downregulated the expression of E-cadherin, TIMP-2 and TIMP-1. The mechanistic study demonstrated that the effect of MCT1 might be correlated with PI3K/Akt signaling pathway. LY294002, a PI3K inhibitor, increased the inhibition of invasion and migration mediated by downregulation of MCT1 in CNE2Z cells. These findings collectively suggested that MCT1 might act as a new regulator to improve invasion and migration of NPC cells and be correlated with activating the PI3K/Akt pathway.
- Published
- 2018
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260. Four Key Steps Control Glycolytic Flux in Mammalian Cells.
- Author
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Tanner LB, Goglia AG, Wei MH, Sehgal T, Parsons LR, Park JO, White E, Toettcher JE, and Rabinowitz JD
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- Animals, Biological Transport, Cell Line, Genes, ras genetics, Genes, ras physiology, Glucose metabolism, Glycolysis genetics, HEK293 Cells, Hexokinase genetics, Humans, Isoenzymes metabolism, Lactic Acid biosynthesis, Mammals, Mice, Models, Biological, NIH 3T3 Cells, Neoplasms enzymology, Glycolysis physiology, Hexokinase metabolism, Phosphofructokinase-1 metabolism
- Abstract
Altered glycolysis is a hallmark of diseases including diabetes and cancer. Despite intensive study of the contributions of individual glycolytic enzymes, systems-level analyses of flux control through glycolysis remain limited. Here, we overexpress in two mammalian cell lines the individual enzymes catalyzing each of the 12 steps linking extracellular glucose to excreted lactate, and find substantial flux control at four steps: glucose import, hexokinase, phosphofructokinase, and lactate export (and not at any steps of lower glycolysis). The four flux-controlling steps are specifically upregulated by the Ras oncogene: optogenetic Ras activation rapidly induces the transcription of isozymes catalyzing these four steps and enhances glycolysis. At least one isozyme catalyzing each of these four steps is consistently elevated in human tumors. Thus, in the studied contexts, flux control in glycolysis is concentrated in four key enzymatic steps. Upregulation of these steps in tumors likely underlies the Warburg effect., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
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261. Muscle hypertrophy following blood flow-restricted, low-force isometric electrical stimulation in rat tibialis anterior: role for muscle hypoxia.
- Author
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Nakajima T, Koide S, Yasuda T, Hasegawa T, Yamasoba T, Obi S, Toyoda S, Nakamura F, Inoue T, Poole DC, and Kano Y
- Subjects
- Animals, Electric Stimulation methods, Hypertrophy metabolism, Hypoxia metabolism, Isometric Contraction physiology, Male, Muscle Contraction physiology, Muscle, Skeletal metabolism, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha metabolism, Rats, Rats, Wistar, Resistance Training methods, Ribosomal Protein S6 metabolism, Signal Transduction physiology, Hypertrophy physiopathology, Hypoxia physiopathology, Muscle, Skeletal physiopathology, Physical Conditioning, Animal physiology, Regional Blood Flow physiology
- Abstract
Low-force exercise training with blood flow restriction (BFR) elicits muscle hypertrophy as seen typically after higher-force exercise. We investigated the effects of microvascular hypoxia [i.e., low microvascular O
2 partial pressures (P mvO2 )] during contractions on muscle hypertrophic signaling, growth response, and key muscle adaptations for increasing exercise capacity. Wistar rats were fitted with a cuff placed around the upper thigh and inflated to restrict limb blood flow. Low-force isometric contractions (30 Hz) were evoked via electrical stimulation of the tibialis anterior (TA) muscle. The P mvO2 was determined by phosphorescence quenching. Rats underwent acute and chronic stimulation protocols. Whereas P mvO2 decreased transiently with 30 Hz contractions, simultaneous BFR induced severe hypoxia, reducing P mvO2 lower than present for maximal (100 Hz) contractions. Low-force electrical stimulation (EXER) induced muscle hypertrophy (6.2%, P < 0.01), whereas control group conditions or BFR alone did not. EXER+BFR also induced an increase in muscle mass (11.0%, P < 0.01) and, unique among conditions studied, significantly increased fiber cross-sectional area in the superficial TA ( P < 0.05). Phosphorylation of ribosomal protein S6 was enhanced by EXER+BFR, as were peroxisome proliferator-activated receptor gamma coactivator-1α and glucose transporter 4 protein levels. Fibronectin type III domain-containing protein 5, cytochrome c oxidase subunit 4, monocarboxylate transporter 1 (MCT1), and cluster of differentiation 147 increased with EXER alone. EXER+BFR significantly increased MCT1 expression more than EXER alone. These data demonstrate that microvascular hypoxia during contractions is not essential for hypertrophy. However, hypoxia induced via BFR may potentiate the muscle hypertrophic response (as evidenced by the increased superficial fiber cross-sectional area) with increased glucose transporter and mitochondrial biogenesis, which contributes to the pleiotropic effects of exercise training with BFR that culminate in an improved capacity for sustained exercise. NEW & NOTEWORTHY We investigated the effects of low microvascular O2 partial pressures (P mvO2 ) during contractions on muscle hypertrophic signaling and key elements in the muscle adaptation for increasing exercise capacity. Although demonstrating that muscle hypoxia is not obligatory for the hypertrophic response to low-force, electrically induced muscle contractions, the reduced P mvO2 enhanced ribosomal protein S6 phosphorylation and potentiated the hypertrophic response. Furthermore, contractions with blood flow restriction increased oxidative capacity, glucose transporter, and mitochondrial biogenesis, which are key determinants of the pleiotropic effects of exercise training.- Published
- 2018
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262. Prefrontal cortex NG2 glia undergo a developmental switch in their responsiveness to exercise.
- Author
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Tomlinson L, Huang PH, and Colognato H
- Subjects
- Animals, Cell Proliferation physiology, Female, Maze Learning physiology, Mice, Inbred C57BL, Monocarboxylic Acid Transporters metabolism, Oligodendroglia cytology, Prefrontal Cortex cytology, Running psychology, Symporters metabolism, Antigens metabolism, Oligodendroglia metabolism, Prefrontal Cortex growth & development, Prefrontal Cortex metabolism, Proteoglycans metabolism, Running physiology
- Abstract
Aerobic exercise is known to influence brain function, e.g., enhancing executive function in both children and adults, with many of these influences being attributed to alterations in neurogenesis and neuronal function. Yet oligodendroglia in adult brains have also been reported to be highly responsive to exercise, including in the prefrontal cortex (PFC), a late myelinating region implicated in working memory. However, whether exercise affects oligodendroglia or myelination in juveniles, either in the PFC or in other brain regions, remains unknown. To address this, both juvenile and young adult mice were provided free access to running wheels for four weeks followed by an analysis of oligodendrocyte development and myelination in the PFC and the corpus callosum, a major white matter tract. Working memory and PFC NG2+ cell development were both affected by exercise in juvenile mice, yet surprisingly these exercise-mediated effects were distinct in juveniles and young adults. In the PFC, NG2+ cell proliferation was increased in exercising juveniles, but not young adults, whereas newly-born oligodendrocyte production was increased in exercising young adults, but not juveniles. Although no overall changes in myelin genes were found, elevated levels of Monocarboxylate Transporter 1, a glial lactate transporter important during active myelination, were found in the PFC of exercising young adults. Overall our findings reveal that long-term exercise modulates PFC glial development and does so differentially in juvenile and young adult mice, providing insight into the cellular responses that may underlie cognitive benefits to teenagers and young adults in response to exercise. © 2018 Wiley Periodicals, Inc. Develop Neurobiol 78: 687-700, 2018., (© 2018 Wiley Periodicals, Inc.)
- Published
- 2018
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263. MCT1 regulates aggressive and metabolic phenotypes in bladder cancer.
- Author
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Zhang G, Zhang Y, Dong D, Wang F, Ma X, Guan F, and Sun L
- Abstract
Background: Monocarboxylate transporter isoform 1 (MCT1) is an important molecule in mediating lactate transportation. Recent studies have shown an oncogenic role of MCT1 in cancer development. Methods: In this study, we aimed to investigate the expression and role of MCT1 in bladder cancer (BCa). MCT1 expression was detected in 124 BCa tissues and their clinicopathological significance was analyzed. We also used The Cancer Genome Atlas database to explore the prognostic association of MCT1 with BCa. Cell proliferation, migration and invasion assays were performed on BCa cells in which MCT1 was downregulated. The effect of MCT1 on BCa cell aerobic glycolysis, as well as its association with HIF-1α, was tested. Results: We found that high MCT1 expression correlated with lymph node and distant metastasis. Patients with high-MCT1 expression showed shorter overall survival than those with low-MCT1 expression. Knockdown of MCT1 inhibited BCa cell proliferation, migration and invasion, and affected expression of epithelial-mesenchymal transition related proteins. Downregulation of MCT1 decreased lactate levels in cell medium, as well as HK2, GLUT1 and LDHB expression. In addition, MCT1 expression was partly dependent on HIF-1α. Conclusions: Taken together, our study has shown a prognostic role of MCT1 in BCa, and provided potential diagnostic and therapeutic options for BCa patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.
- Published
- 2018
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264. Glucose-dependent growth arrest of leukemia cells by MCT1 inhibition: Feeding Warburg's sweet tooth and blocking acid export as an anticancer strategy.
- Author
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Pivovarova AI and MacGregor GG
- Subjects
- Antineoplastic Agents metabolism, Antineoplastic Agents pharmacology, Cell Cycle Checkpoints drug effects, Glucose pharmacology, Humans, K562 Cells, MCF-7 Cells, Thiophenes pharmacology, Uracil analogs & derivatives, Uracil pharmacology, Cell Cycle Checkpoints physiology, Glucose metabolism, Growth Inhibitors pharmacology, Leukemia metabolism, Monocarboxylic Acid Transporters antagonists & inhibitors, Monocarboxylic Acid Transporters metabolism, Symporters antagonists & inhibitors, Symporters metabolism
- Abstract
This study aims to investigate the utilization of The Warburg Effect, cancer's "sweet tooth" and natural greed for glucose to enhance the effect of monocarboxylate transporter inhibition on cellular acidification. By simulating hyperglycemia with high glucose we may increase the effectiveness of inhibition of lactate and proton export on the dysregulation of cell pH homeostasis causing cell death or disruption of growth in cancer cells. MCT1 and MCT4 expression was determined in MCF7 and K562 cell lines using RT-PCR. Cell viability, growth, intracellular pH and cell cycle analysis was measured in the cell lines grown in 5 mM and 25 mM glucose containing media in the presence and absence of the MCT1 inhibitor AR-C155858 (1 μM) and the NHE1 inhibitor cariporide (10 μM). The MCT1 inhibitor, AR-C155858 had minimal effect on the viability, growth and intracellular pH of MCT4 expressing MCF7 cells. AR-C155858 had no effect on the viability of the MCT1 expressing K562 cells, but decreased intracellular pH and cell proliferation, by a glucose-dependent mechanism. Inhibition of NHE1 on its own had a no effect on cell growth, but together with AR-C155858 showed an additive effect on inhibition of cell growth. In cancer cells that only express MCT1, increased glucose concentrations in the presence of an MCT1 inhibitor decreased intracellular pH and reduced cell growth by G1 phase cell-cycle arrest. Thus we propose a transient hyperglycemic-clamp in combination with proton export inhibitors be evaluated as an adjunct to cancer treatment in clinical studies., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)
- Published
- 2018
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265. Fenugreek galactomannan and citrus pectin improve several parameters associated with glucose metabolism and modulate gut microbiota in mice.
- Author
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Shtriker MG, Hahn M, Taieb E, Nyska A, Moallem U, Tirosh O, and Madar Z
- Subjects
- AMP-Activated Protein Kinases metabolism, Animals, Blood Glucose analysis, Cecum metabolism, Dietary Fiber administration & dosage, Fatty Acids, Volatile analysis, Galactose analogs & derivatives, Gastrointestinal Microbiome physiology, Glucose Tolerance Test, Liver enzymology, Male, Mice, Mice, Inbred C57BL, Propionates analysis, Blood Glucose metabolism, Diet, Gastrointestinal Microbiome drug effects, Mannans administration & dosage, Pectins administration & dosage, Trigonella chemistry
- Abstract
Objective: Galactomannans derived from fenugreek confer known health benefits; however, there is little information regarding health benefits of citrus pectin (CP) and its association with gut microbiome metabolites. The aim of this study was to examine links between galactomannan and CP consumption, microbiota development, and glucose metabolism., Design: Male C57 BL/6 J mice ages 7 to 8 wk were fed ad libitum with a normal diet or one supplemented with 15% of either galactomannan or CP. At 3 wk, an oral glucose tolerance test was performed. Animals were sacrificed at 4 wk and relevant organs were harvested., Results: Fiber enrichment led to reductions in weight gain, fasting glucose levels, and total serum cholesterol (P < 0.05). Compared with mice fed the normal diet, microbiota populations were altered in both fiber groups and were found to be richer in Bacteroidetes rather than Firmicutes (P < 0.05). The modification was significantly greater in galactomannan-fed than in CP-fed mice (P < 0.0001). Also, enhanced levels of the short-chain fatty acid (SCFA) propionate were found in the cecal contents of CP-fed animals (P < 0.05). Protein expression levels of monocarboxylate transporter 1, which may promote transport of SCFA, were measured in the large intestines after fiber consumption. Enhanced adenosine monophosphate-activated protein kinase (AMPK) activation was observed in livers of galactomannan-fed mice (P < 0.05)., Conclusion: Consumption of diets containing soluble fibers, as used in this study, resulted in gut microbiota comprising a healthier flora, and led to positive effects on weight, glycemic control, and liver β oxidation via AMPK., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2018
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266. Anti-proliferative effect of Zea mays L. cob extract on rat C6 glioma cells through regulation of glycolysis, mitochondrial ROS, and apoptosis.
- Author
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Hwang E, Sim S, Park SH, Song KD, Lee HK, Heo TH, Jun HS, and Kim SJ
- Subjects
- Animals, Brain Neoplasms drug therapy, Brain Neoplasms metabolism, Cell Cycle Checkpoints drug effects, Cell Line, Tumor, Cell Survival drug effects, Cyclin-Dependent Kinase Inhibitor p21 metabolism, G1 Phase drug effects, Glioma metabolism, Mice, Monocarboxylic Acid Transporters metabolism, NIH 3T3 Cells, Rats, Symporters metabolism, Apoptosis drug effects, Cell Proliferation drug effects, Glioma drug therapy, Glycolysis drug effects, Mitochondria drug effects, Plant Extracts pharmacology, Reactive Oxygen Species metabolism, Zea mays chemistry
- Abstract
Gliomas are one of the most common types of primary brain tumors, characterized by rapid proliferation and infiltration into normal brain tissue. Corncob is the most plentiful byproducts of Zea mays L., of which anti-cancer effect has not been reported. Therefore, we aimed to examine the anti-proliferative effect of a high-pressure hot-water extract of corncob on glioma cells and elucidated the underlying mechanism. The high-pressure hot-water corncob extract contained approximately 94.8 mg/g and 1.82 μg/g of total phenol and catechin, respectively. Glioma cell treated with different concentrations of high-pressure hot-water corncob extract was shown to be suppressed in growth during three days of culture. In parallel, corncob extract reduced the glioma cell viability and induced cell cycle arrest in G0/G1 phase by upregulating the expression level of cyclin-dependent kinase inhibitor p21. Decreased proliferation and viability in glioma cells treated with corncob extract can be attributed to reduced reactive oxygen species (ROS), antiapoptotic Bcl-2 protein, and a lactate transporter monocarboxylate transporter 1 of which levels are higher than those in normal cells. Based on its inhibitory effects on proliferation and viability of C6 glioma cells, a high-pressure hot-water corncob extract has the potential to be used for glioma treatment., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)
- Published
- 2018
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267. Autophagy promotes metastasis and glycolysis by upregulating MCT1 expression and Wnt/β-catenin signaling pathway activation in hepatocellular carcinoma cells.
- Author
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Fan Q, Yang L, Zhang X, Ma Y, Li Y, Dong L, Zong Z, Hua X, Su D, Li H, and Liu J
- Subjects
- Carcinoma, Hepatocellular pathology, Cell Line, Tumor, Cell Proliferation, Gene Expression, Genes, Reporter, Glucose metabolism, Glycolysis, Humans, Liver Neoplasms pathology, Models, Biological, Autophagy genetics, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular metabolism, Gene Expression Regulation, Neoplastic, Liver Neoplasms genetics, Liver Neoplasms metabolism, Monocarboxylic Acid Transporters genetics, Symporters genetics, Wnt Signaling Pathway
- Abstract
Background: Autophagy is a dynamic physiological process that can generate energy and nutrients for cell survival during stress. Autophagy can regulate the migration and invasive ability in cancer cells. However, the connection between autophagy and metabolism is unclear. Monocarboxylate transporter 1 (MCT1) plays an important role in lactic acid transport and H
+ clearance in cancer cells, and Wnt/β-catenin signaling can increase cancer cell glycolysis. We investigated whether autophagy promotes glycolysis in hepatocellular carcinoma (HCC) cells by activating the Wnt/β-catenin signaling pathway, accompanied by MCT1 upregulation., Methods: Autophagic activity was evaluated using western blotting, immunoblotting, and transmission electron microscopy. The underlying mechanisms of autophagy activation on HCC cell glycolysis were studied via western blotting, and Transwell, lactate, and glucose assays. MCT1 expression was detected using quantitative reverse transcription-PCR (real-time PCR), western blotting, and immunostaining of HCC tissues and the paired adjacent tissues., Results: Autophagy promoted HCC cell glycolysis accompanied by MCT1 upregulation. Wnt/β-catenin signaling pathway activation mediated the effect of autophagy on HCC cell glycolysis. β-Catenin downregulation inhibited the autophagy-induced glycolysis in HCC cells, and reduced MCT1 expression in the HCC cells. MCT1 was highly expressed in HCC tissues, and high MCT1 expression correlated positively with the expression of microtubule-associated protein light chain 3 (LC3)., Conclusion: Activation of autophagy can promote metastasis and glycolysis in HCC cells, and autophagy induces MCT1 expression by activating Wnt/β-catenin signaling. Our study describes the connection between autophagy and glucose metabolism in HCC cells and may provide a potential therapeutic target for HCC treatment.- Published
- 2018
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268. Impact of MCT1 Haploinsufficiency on the Mouse Retina.
- Author
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Peachey NS, Yu M, Han JYS, Lengacher S, Magistretti PJ, Pellerin L, and Philp NJ
- Subjects
- Animals, Electroretinography, Energy Metabolism, Evoked Potentials, Visual, Heterozygote, Lactates metabolism, Mice, Mice, Inbred C57BL, Mice, Transgenic, Monocarboxylic Acid Transporters genetics, Monocarboxylic Acid Transporters metabolism, Motor Neurons metabolism, Oligodendroglia metabolism, Retinal Bipolar Cells metabolism, Symporters genetics, Symporters metabolism, Monocarboxylic Acid Transporters deficiency, Photoreceptor Cells, Vertebrate metabolism, Retina metabolism, Symporters deficiency
- Abstract
The monocarboxylate transporter 1 (MCT1) is highly expressed in the outer retina, suggesting that it plays a critical role in photoreceptors. We examined MCT1
+/- heterozygotes, which express half of the normal complement of MCT1. The MCT1+/- retina developed normally and retained normal function, indicating that MCT1 is expressed at sufficient levels to support outer retinal metabolism.- Published
- 2018
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269. Branched-chain ketoacids secreted by glioblastoma cells via MCT1 modulate macrophage phenotype.
- Author
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Silva LS, Poschet G, Nonnenmacher Y, Becker HM, Sapcariu S, Gaupel AC, Schlotter M, Wu Y, Kneisel N, Seiffert M, Hell R, Hiller K, Lichter P, and Radlwimmer B
- Subjects
- Biological Transport, Cell Count, Cell Line, Tumor, Glioblastoma immunology, Humans, In Vitro Techniques, Macrophages immunology, Macrophages pathology, Monocarboxylic Acid Transporters antagonists & inhibitors, Monocarboxylic Acid Transporters deficiency, Monocarboxylic Acid Transporters genetics, Muscle Proteins deficiency, Muscle Proteins genetics, Phagocytosis, Phenotype, Pyruvic Acid metabolism, Symporters antagonists & inhibitors, Symporters genetics, Transaminases, Amino Acids, Branched-Chain metabolism, Glioblastoma physiopathology, Macrophages physiology, Monocarboxylic Acid Transporters metabolism, Symporters metabolism
- Abstract
Elevated amino acid catabolism is common to many cancers. Here, we show that glioblastoma are excreting large amounts of branched-chain ketoacids (BCKAs), metabolites of branched-chain amino acid (BCAA) catabolism. We show that efflux of BCKAs, as well as pyruvate, is mediated by the monocarboxylate transporter 1 (MCT1) in glioblastoma. MCT1 locates in close proximity to BCKA-generating branched-chain amino acid transaminase 1, suggesting possible functional interaction of the proteins. Using in vitro models, we demonstrate that tumor-excreted BCKAs can be taken up and re-aminated to BCAAs by tumor-associated macrophages. Furthermore, exposure to BCKAs reduced the phagocytic activity of macrophages. This study provides further evidence for the eminent role of BCAA catabolism in glioblastoma by demonstrating that tumor-excreted BCKAs might have a direct role in tumor immune suppression. Our data further suggest that the anti-proliferative effects of MCT1 knockdown observed by others might be related to the blocked excretion of BCKAs., (© 2017 The Authors.)
- Published
- 2017
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270. Inner Blood-Retinal Barrier Dominantly Expresses Breast Cancer Resistance Protein: Comparative Quantitative Targeted Absolute Proteomics Study of CNS Barriers in Pig.
- Author
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Zhang Z, Uchida Y, Hirano S, Ando D, Kubo Y, Auriola S, Akanuma SI, Hosoya KI, Urtti A, Terasaki T, and Tachikawa M
- Subjects
- ATP Binding Cassette Transporter, Subfamily G, Member 2 metabolism, Animals, Biological Transport, Cell Membrane metabolism, Humans, Neoplasm Proteins metabolism, Sodium-Potassium-Exchanging ATPase metabolism, Swine, ATP-Binding Cassette Transporters metabolism, Blood-Brain Barrier metabolism, Blood-Retinal Barrier metabolism, Membrane Transport Proteins metabolism, Proteomics methods
- Abstract
The purpose of this study was to determine absolute protein expression levels of transporters at the porcine inner blood-retinal barrier (BRB) and to compare the transporter protein expression quantitatively among the inner BRB, outer BRB, blood-brain barrier (BBB), and blood-cerebrospinal fluid barrier (BCSFB). Crude membrane fractions of isolated retinal capillaries (inner BRB) and isolated retinal pigment epithelium (RPE, outer BRB) were prepared from porcine eyeballs, while plasma membrane fractions were prepared from isolated porcine brain capillaries (BBB) and isolated choroid plexus (BCSFB). Protein expression levels of 32 molecules, including 16 ATP-binding-cassette (ABC) transporters and 13 solute-carrier (SLC) transporters, were measured using a quantitative targeted absolute proteomic technique. At the inner BRB, five molecules were detected: breast cancer resistance protein (BCRP, ABCG2; 22.8 fmol/μg protein), multidrug resistance protein 1 (MDR1, ABCB1; 8.70 fmol/μg protein), monocarboxylate transporter 1 (MCT1, SLC16A1; 4.83 fmol/μg protein), glucose transporter 1 (GLUT1, SLC2A1; 168 fmol/μg protein), and sodium-potassium adenosine triphosphatase (Na
+ /K+ -ATPase; 53.7 fmol/μg protein). Other proteins were under the limits of quantification. Expression of MCT1 was at least 17.6-, 11.0-, and 19.2-fold greater than those of MCT2, 3, and 4, respectively. The transporter protein expression at the inner BRB was most highly correlated with that at the BBB (R2 = 0.8906), followed by outer BRB (R2 = 0.7988) and BCSFB (R2 = 0.4730). Sodium-dependent multivitamin transporter (SMVT, SLC5A6) and multidrug resistance-associated protein 1 (MRP1, ABCC1) were expressed at the outer BRB (0.378 and 1.03 fmol/μg protein, respectively) but were under the limit of quantification at the inner BRB. These findings may be helpful for understanding differential barrier function.- Published
- 2017
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271. Lactate stimulates CA IX expression in normoxic cancer cells.
- Author
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Panisova E, Kery M, Sedlakova O, Brisson L, Debreova M, Sboarina M, Sonveaux P, Pastorekova S, and Svastova E
- Abstract
Besides hypoxia, other factors and molecules such as lactate, succinate, and reactive oxygen species activate transcription factor hypoxia-inducible factor-1 (HIF-1) even in normoxia. One of the main target gene products of HIF-1 is carbonic anhydrase IX (CA IX). CA IX is overexpressed in many tumors and serves as prognostic factor for hypoxic, aggressive and malignant cancers. CA IX is also induced in normoxia in high cell density. In this study, we observed that lactate induces CA IX expression in normoxic cancer cells in vitro and in vivo . We further evidenced that participation of both HIF-1 and specificity protein 1 (SP1) transcription factors is crucial for lactate-driven normoxic induction of the CA9 gene. By inducing CA IX, lactate can facilitate the maintenance of cancer cell aggressive behavior in normoxia., Competing Interests: CONFLICTS OF INTEREST The authors have declared that no conflicts of interest exists.
- Published
- 2017
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272. Monocarboxylate transporter 1 (MCT1), a tool to stratify acute myeloid leukemia (AML) patients and a vehicle to kill cancer cells.
- Author
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Lopes-Coelho F, Nunes C, Gouveia-Fernandes S, Rosas R, Silva F, Gameiro P, Carvalho T, Gomes da Silva M, Cabeçadas J, Dias S, Gonçalves LG, and Serpa J
- Abstract
Dysregulation of glucose/lactate dynamics plays a role in cancer progression, and MCTs are key elements in metabolic remodeling. VEGF is a relevant growth factor in the maintenance of bone marrow microenvironment and it is also important in hematological diseases. Our aim was to investigate the role of VEGF in the metabolic adaptation of Acute myeloid leukemia (AML) cells by evaluating the metabolic profiles and cell features according to the AML lineage and testing lactate as a metabolic coin. Our in vitro results showed that AML promyelocytic (HL60) and monocytic (THP1) (but not erythroid- HEL) lineages are well adapted to VEGF and lactate rich environment. Their metabolic adaptation relies on high rates of glycolysis to generate intermediates for PPP to support cell proliferation, and on the consumption of glycolysis-generated lactate to supply biomass and energy production. VEGF orchestrates this metabolic network by regulating MCT1 expression. Bromopyruvic acid (BPA) was proven to be an effective cytotoxic in AML, possibly transported by MCT1. Our study reinforces that targeting metabolism can be a good strategy to fight cancer. MCT1 expression at the time of diagnosis can assist on the identification of AML patients that will benefit from BPA therapy. Additionally, MCT1 can be used in targeted delivery of conventional cytotoxic drugs., Competing Interests: CONFLICTS OF INTEREST The authors disclaim any conflicts of interest.
- Published
- 2017
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273. T84 monolayers are superior to Caco-2 as a model system of colonocytes.
- Author
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Devriese S, Van den Bossche L, Van Welden S, Holvoet T, Pinheiro I, Hindryckx P, De Vos M, and Laukens D
- Subjects
- Animals, Caco-2 Cells, Humans, Tumor Cells, Cultured, Colon pathology, Models, Biological
- Abstract
Colonic adenocarcinoma-derived Caco-2 and T84 epithelial cell lines are frequently used as in vitro model systems of functional epithelial barriers. Both are utilised interchangeably despite evidence that differentiated Caco-2 cells are more reminiscent of small intestinal enterocytes than of colonocytes, whereas differentiated T84 cells are less well characterised. The aim of this study was, therefore, to further characterise and compare differentiated Caco-2 and T84 cells. The objectives were to (1) compare the brush border morphology, (2) measure the expression of enterocyte- and colonocyte-specific genes and (3) compare their response to butyrate, which is dependent on the monocarboxylate transporter 1 (MCT1), an apical protein expressed primarily in colonocytes. T84 microvilli were significantly shorter than those of Caco-2 cells, which is a characteristic difference between small intestinal enterocytes and colonocytes. Also, enterocyte-associated brush border enzymes expressed in differentiated Caco-2 cells were not increased during T84 maturation, whereas colonic markers such as MCT1 were more abundant in differentiated T84 cells compared to differentiated Caco-2 cells. Consequently, T84 cells displayed a dose-responsive improvement of barrier function towards butyrate, which was absent in Caco-2 cells. On the other hand, differences in epithelial toll-like receptor expression between Caco-2 and T84 monolayers did not result in a corresponding differential functional response. We conclude that differentiated Caco-2 and T84 cells have distinct morphological, biochemical and functional characteristics, suggesting that T84 cells do not acquire the biochemical signature of mature small intestinal enterocytes like Caco-2 cells, but retain much of their original colonic characteristics throughout differentiation. These findings can help investigators select the appropriate intestinal epithelial cell line for specific in vitro research purposes.
- Published
- 2017
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274. Pre-clinical pharmacology of AZD3965, a selective inhibitor of MCT1: DLBCL, NHL and Burkitt's lymphoma anti-tumor activity.
- Author
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Curtis NJ, Mooney L, Hopcroft L, Michopoulos F, Whalley N, Zhong H, Murray C, Logie A, Revill M, Byth KF, Benjamin AD, Firth MA, Green S, Smith PD, and Critchlow SE
- Abstract
Tumors frequently display a glycolytic phenotype with increased flux through glycolysis and concomitant synthesis of lactate. To maintain glycolytic flux and prevent intracellular acidification, tumors efflux lactate via lactate transporters (MCT1-4). Inhibitors of lactate transport have the potential to inhibit glycolysis and tumor growth. We developed a small molecule inhibitor of MCT1 (AZD3965) and assessed its activity across a panel of cell lines. We explored its antitumor activity as monotherapy and in combination with doxorubicin or rituximab. AZD3965 is a potent inhibitor of MCT1 with activity against MCT2 but selectivity over MCT3 and MCT4. In vitro , AZD3965 inhibited the growth of a range of cell lines especially haematological cells. Inhibition of MCT1 by AZD3965 inhibited lactate efflux and resulted in accumulation of glycolytic intermediates. In vivo , AZD3965 caused lactate accumulation in the Raji Burkitt's lymphoma model and significant tumor growth inhibition. Moreover, AZD3965 can be combined with doxorubicin or rituximab, components of the R-CHOP standard-of-care in DLBCL and Burkitt's lymphoma. Finally, combining lactate transport inhibition by AZD3965 with GLS1 inhibition in vitro , enhanced cell growth inhibition and cell death compared to monotherapy treatment. The ability to combine AZD3965 with novel, and standard-of-care inhibitors offers novel combination opportunities in haematological cancers., Competing Interests: CONFLICTS OF INTEREST All authors are current or former employees of AstraZeneca.
- Published
- 2017
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275. MACC1 mediates chemotherapy sensitivity of 5-FU and cisplatin via regulating MCT1 expression in gastric cancer.
- Author
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Wang C, Wen Z, Xie J, Zhao Y, Zhao L, Zhang S, Liu Y, Xue Y, and Shi M
- Subjects
- Antineoplastic Agents pharmacology, Blotting, Western, Cell Line, Tumor, Cell Survival drug effects, Cell Survival genetics, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Monocarboxylic Acid Transporters antagonists & inhibitors, Monocarboxylic Acid Transporters metabolism, Multivariate Analysis, Prognosis, Pyrimidinones pharmacology, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction, Stomach Neoplasms metabolism, Stomach Neoplasms pathology, Symporters antagonists & inhibitors, Symporters metabolism, Thiophenes pharmacology, Trans-Activators, Transcription Factors metabolism, Cisplatin pharmacology, Fluorouracil pharmacology, Gene Expression Regulation, Neoplastic drug effects, Monocarboxylic Acid Transporters genetics, Stomach Neoplasms genetics, Symporters genetics, Transcription Factors genetics
- Abstract
Chemotherapeutic insensitivity is a main obstacle for effective treatment of gastric cancer (GC), the underlying mechanism remains to be investigated. Metastasis-associated in colon cancer-1 (MACC1), a transcription factor highly expressed in GC, is found to be related to chemotherapy sensitivity. Monocarboxylate transporter 1 (MCT1), a plasma membrane protein co-transporting lactate and H
+ , mediates drug sensitivity by regulating lactate metabolism. Targeting MCT1 has recently been regarded as a promising way to treat cancers and MCT1 inhibitor has entered the clinical trial for GC treatment. However, the correlation of these two genes and their combined effects on chemotherapy sensitivity has not been clarified. In this study, we found that MACC1 and MCT1 were both highly expressed in GC and exhibited a positive correlation in clinical samples. Further, we demonstrated that MACC1 could mediate sensitivity of 5-FU and cisplatin in GC cells, and MACC1 mediated MCT1 regulation was closely related to this sensitivity. A MCT1 inhibitor AZD3965 recovered the sensitivity of 5-FU and cisplatin in GC cells which overexpressed MACC1. These results suggested that MACC1 could influence the chemotherapy sensitivity by regulating MCT1 expression, providing new ideas and strategy for GC treatment., (Copyright © 2017 Elsevier Inc. All rights reserved.)- Published
- 2017
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276. Intratumoral lactate metabolism in Barrett's esophagus and adenocarcinoma.
- Author
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Huhta H, Helminen O, Palomäki S, Kauppila JH, Saarnio J, Lehenkari PP, and Karttunen TJ
- Subjects
- Adenocarcinoma pathology, Adult, Aged, Aged, 80 and over, Barrett Esophagus pathology, Electron Transport Complex IV, Esophageal Neoplasms pathology, Female, Humans, Male, Middle Aged, Monocarboxylic Acid Transporters metabolism, Muscle Proteins metabolism, Survival Analysis, Symporters metabolism, Adenocarcinoma metabolism, Barrett Esophagus metabolism, Esophageal Neoplasms metabolism, Lactates metabolism
- Abstract
Background: Monocarboxylate transporters (MCTs) are cell membrane proteins which transport pyruvate, lactate and ketone bodies across the plasma membrane. MCTs are activated in various cancers, but their expression in esophageal adenocarcinoma is not known. The present study was conducted to elucidate the expression of MCTs in esophageal adenocarcinoma and its precursor lesions., Results: Cytoplasmic MCT1, MCT4 and MTCO1 expression linearly increased from normal epithelium to Barrett's mucosa to dysplasia and cancer. Low cytoplasmic MCT1 expression associated with high T-class (P < 0.01), positive lymph node metastases (P < 0.05), positive distant metastases (P < 0.01) and high tumor stage (P < 0.01). High cytoplasmic MCT4 expression correlated significantly with positive distant metastases (P < 0.05). Both low MCT1 and high MCT4 histoscore predicted survival in univariate analysis (P < 0.01). MCT4 histoscore predicted survival in multivariate analysis (P = 0.043; HR 1.8 95%CI 1.0-3.1). MTCO1 expression was not correlated to clinicopathological variables or survival., Materials and Methods: MCT1, MCT4 and mitochondrial cytochrome c oxidase (MTCO1) expression were determined with immunohistochemistry in esophageal specimens from 129 patients with columnar dysplasia or adenocarcinoma. Specimens including normal esophagus (n = 88), gastric (n = 67) or intestinal metaplasia (n = 51), low-grade (n = 42), high-grade dysplasia (n = 37) and esophageal adenocarcinoma (n = 99) were evaluated., Conclusions: Major increase in markers of tumor metabolism occurs during carcinogenesis and progression of esophageal adenocarcinoma. MCT1 and MCT4 are prognostic factors in esophageal adenocarcinoma.
- Published
- 2017
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277. Organized metabolic crime in prostate cancer: The coexpression of MCT1 in tumor and MCT4 in stroma is an independent prognosticator for biochemical failure.
- Author
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Andersen, Sigve, Solstad, Ørjan, Moi, Line, Donnem, Tom, Eilertsen, Marte, Nordby, Yngve, Ness, Nora, Richardsen, Elin, Busund, Lill-Tove, and Bremnes, Roy M.
- Subjects
- *
PROSTATE cancer , *CELL membranes , *GENE expression , *LACTATES , *BIOMARKERS , *COHORT analysis - Abstract
Background Lactate import or export over cell membranes is facilitated by monocarboxylate transporters (MCTs) 1 and 4. Expression profiles can be markers of an oxidative or glycolytic phenotype. Descriptive studies and functional studies in neoplastic cells and fibroblasts in prostate cancer (PC) have suggested a distinct phenotype. We aimed to explore expression of MCT1 and MCT4 in PC cells and surrounding stroma in a large cohort. Additionally, we wanted to find out if distinct expression profiles were associated with biochemical failure–free survival (BFFS). Methods Tissue microarrays were constructed from 535 patients with radical prostatectomies between January 1, 1995, and December 31, 2005. Immunohistochemistry was used to detect expression, and degrees of expression were evaluated semiquantitatively by 2 pathologists using light microscopy. Results For MCT1, there was only epithelial expression, whereas there was a low level of expression of MCT4 in tumor and stroma. A total of 172 patients had a low expression of MCT1 in tumor and MCT4 in stroma. There were 232 patients who had a high expression of MCT1 and a low expression of MCT4 in stroma. Only 11 patients had a low tumoral MCT1 expression and a high stromal MCT4 expression, and 26 patients (5%) had a high expression of both. Patients with a high-high combination had a significantly reduced BFFS ( P = 0.011), and when adjusting for other factors, its effect was significant and independent (HR = 1.99, CI 95%: 1.09–3.62; P = 0.024). Conclusions This study adds to the current understanding of the reversed Warburg effect to be a significant phenotype in PC. High coexpression of MCT1 in tumor and MCT4 in stroma is independently associated to a worse BFFS, and the strength of this association is as strong as having a Gleason score of≥9. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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278. A ketogenic diet increases transport and oxidation of ketone bodies in RG2 and 9L gliomas without affecting tumor growth.
- Author
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De Feyter HM, Behar KL, Rao JU, Madden-Hennessey K, Ip KL, Hyder F, Drewes LR, Geschwind JF, de Graaf RA, and Rothman DL
- Subjects
- Animals, Cell Line, Tumor, Disease Models, Animal, Ketone Bodies metabolism, Male, Monocarboxylic Acid Transporters metabolism, Rats, Inbred F344, Survival Analysis, Symporters metabolism, Tumor Burden, 3-Hydroxybutyric Acid metabolism, Brain Neoplasms drug therapy, Brain Neoplasms metabolism, Diet, Ketogenic, Glioma diet therapy, Glioma metabolism
- Abstract
Background: The dependence of tumor cells, particularly those originating in the brain, on glucose is the target of the ketogenic diet, which creates a plasma nutrient profile similar to fasting: increased levels of ketone bodies and reduced plasma glucose concentrations. The use of ketogenic diets has been of particular interest for therapy in brain tumors, which reportedly lack the ability to oxidize ketone bodies and therefore would be starved during ketosis. Because studies assessing the tumors' ability to oxidize ketone bodies are lacking, we investigated in vivo the extent of ketone body oxidation in 2 rodent glioma models., Methods: Ketone body oxidation was studied using (13)C MR spectroscopy in combination with infusion of a (13)C-labeled ketone body (beta-hydroxybutyrate) in RG2 and 9L glioma models. The level of ketone body oxidation was compared with nontumorous cortical brain tissue., Results: The level of (13)C-beta-hydroxybutyrate oxidation in 2 rat glioma models was similar to that of contralateral brain. In addition, when glioma-bearing animals were fed a ketogenic diet, the ketone body monocarboxylate transporter was upregulated, facilitating uptake and oxidation of ketone bodies in the gliomas., Conclusions: These results demonstrate that rat gliomas can oxidize ketone bodies and indicate upregulation of ketone body transport when fed a ketogenic diet. Our findings contradict the hypothesis that brain tumors are metabolically inflexible and show the need for additional research on the use of ketogenic diets as therapy targeting brain tumor metabolism., (© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2016
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279. Regulation of colonic epithelial butyrate transport: Focus on colorectal cancer.
- Author
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Gonçalves P and Martel F
- Abstract
Highlights: Fermentation of the dietary fiber by intestinal microflora results in production of butyrate.Butyrate possesses anticarcinogenic effect at the colonic level.Three transporters (MCT1, SMCT1 and BCRP) regulate the intracellular concentration of BT in colonic epithelial cells.Changes in the expression of these transporters occur in colorectal cancer., Abstract: Colorectal cancer (CRC) is one of the most common solid tumors worldwide. Consumption of dietary fiber is associated with a low risk of developing CRC. The fermentation of the dietary fiber by intestinal microflora results in production of butyrate (BT). This short-chain fatty acid is an important metabolic substrate in normal colonic epithelial cells and has important homeostatic functions at the colonic level. Because the cellular effects of BT (e.g. inhibition of histone deacetylases) are dependent on its intracellular concentration, knowledge on the mechanisms involved in BT membrane transport and its regulation seems particularly relevant. In this review, we will present the carrier-mediated mechanisms involved in BT membrane transport at the colonic epithelial level and their regulation, with an emphasis on CRC. Several xenobiotics known to modulate the risk for developing CRC are able to interfere with BT transport at the intestinal level. Thus, interference with BT transport certainly contributes to the anticarcinogenic or procarcinogenic effect of these compounds and these compounds may interfere with the anticarcinogenic effect of BT. Finally, we suggest that differences in BT transport between normal colonocytes and tumoral cells contribute to the "BT paradox" (the apparent opposing effect of BT in CRC cells and normal colonocytes)., (Copyright 2016 PBJ-Associação Porto Biomedical/Porto Biomedical Society.)
- Published
- 2016
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280. Mutant IDH1 expression is associated with down-regulation of monocarboxylate transporters.
- Author
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Viswanath P, Najac C, Izquierdo-Garcia JL, Pankov A, Hong C, Eriksson P, Costello JF, Pieper RO, and Ronen SM
- Subjects
- Brain Neoplasms genetics, Brain Neoplasms pathology, Down-Regulation, Gene Expression Regulation, Neoplastic genetics, Glioma genetics, Glioma pathology, Humans, Mutation, Brain Neoplasms metabolism, Glioma metabolism, Isocitrate Dehydrogenase genetics, Monocarboxylic Acid Transporters biosynthesis, Muscle Proteins biosynthesis, Symporters biosynthesis
- Abstract
Mutations in isocitrate dehydrogenase 1 (IDH1) are characteristic of low-grade gliomas. We recently showed that mutant IDH1 cells reprogram cellular metabolism by down-regulating pyruvate dehydrogenase (PDH) activity. Reduced pyruvate metabolism via PDH could lead to increased pyruvate conversion to lactate. The goal of this study was therefore to investigate the impact of the IDH1 mutation on the pyruvate-to-lactate flux. We used 13C magnetic resonance spectroscopy and compared the conversion of hyperpolarized [1-13C]-pyruvate to [1-13C]-lactate in immortalized normal human astrocytes expressing mutant or wild-type IDH1 (NHAIDHmut and NHAIDHwt). Our results indicate that hyperpolarized lactate production is reduced in NHAIDHmut cells compared to NHAIDHwt. This reduction was associated with lower expression of the monocarboxylate transporters MCT1 and MCT4 in NHAIDHmut cells. Furthermore, hyperpolarized lactate production was comparable in lysates of NHAIDHmut and NHAIDHwt cells, wherein MCTs do not impact hyperpolarized pyruvate delivery and lactate production. Collectively, our findings indicated that lower MCT expression was a key contributor to lower hyperpolarized lactate production in NHAIDHmut cells. The SLC16A3 (MCT4) promoter but not SLC16A1 (MCT1) promoter was hypermethylated in NHAIDHmut cells, pointing to possibly different mechanisms mediating reduced MCT expression. Finally analysis of low-grade glioma patient biopsy data from The Cancer Genome Atlas revealed that MCT1 and MCT4 expression was significantly reduced in mutant IDH1 tumors compared to wild-type. Taken together, our study shows that reduced MCT expression is part of the metabolic reprogramming of mutant IDH1 gliomas. This finding could impact treatment and has important implications for metabolic imaging of mutant IDH1 gliomas., Competing Interests: The authors declare no conflicts of interest.
- Published
- 2016
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281. Monocarboxylate transporter 1 contributes to growth factor-induced tumor cell migration independent of transporter activity.
- Author
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Gray AL, Coleman DT, Shi R, and Cardelli JA
- Subjects
- Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Humans, Lactic Acid metabolism, Monocarboxylic Acid Transporters genetics, Muscle Proteins genetics, Muscle Proteins metabolism, Neoplasm Invasiveness, Phosphorylation, Proto-Oncogene Proteins c-met metabolism, RNA Interference, Signal Transduction, Symporters genetics, Time Factors, Transfection, Cell Movement drug effects, Epidermal Growth Factor pharmacology, Hepatocyte Growth Factor pharmacology, Monocarboxylic Acid Transporters metabolism, Symporters metabolism
- Abstract
Tumor progression to metastatic disease contributes to the vast majority of incurable cancer. Understanding the processes leading to advanced stage cancer is important for the development of future therapeutic strategies. Here, we establish a connection between tumor cell migration, a prerequisite to metastasis, and monocarboxylate transporter 1 (MCT1). MCT1 transporter activity is known to regulate aspects of tumor progression and, as such, is a clinically relevant target for treating cancer. Knockdown of MCT1 expression caused decreased hepatocyte growth factor (HGF)-induced as well as epidermal growth factor (EGF)-induced tumor cell scattering and wound healing. Western blot analysis suggested that MCT1 knockdown (KD) hinders signaling through the HGF receptor (c-Met) but not the EGF receptor. Exogenous, membrane-permeable MCT1 substrates were not able to rescue motility in MCT1 KD cells, nor was pharmacologic inhibition of MCT1 able to recapitulate decreased cell motility as seen with MCT1 KD cells, indicating transporter activity of MCT1 was dispensable for EGF- and HGF-induced motility. These results indicate MCT1 expression, independent of transporter activity, is required for growth factor-induced tumor cell motility. The findings presented herein suggest a novel function for MCT1 in tumor progression independent of its role as a monocarboxylate transporter., Competing Interests: The authors have no relevant conflicts of interest to disclose.
- Published
- 2016
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282. STAT3:FOXM1 and MCT1 drive uterine cervix carcinoma fitness to a lactate-rich microenvironment.
- Author
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Silva LS, Goncalves LG, Silva F, Domingues G, Maximo V, Ferreira J, Lam EW, Dias S, Felix A, and Serpa J
- Subjects
- Adenocarcinoma genetics, Adenocarcinoma pathology, Animals, Carcinoma, Squamous Cell metabolism, Carcinoma, Squamous Cell pathology, Cell Cycle Proteins biosynthesis, Cervix Uteri pathology, Female, Forkhead Box Protein M1 biosynthesis, Forkhead Box Protein O3 biosynthesis, Gene Expression Regulation, Neoplastic, HeLa Cells, Humans, Lactic Acid metabolism, Mice, Oncogene Proteins biosynthesis, STAT3 Transcription Factor biosynthesis, Signal Transduction, Tumor Microenvironment genetics, Uterine Cervical Neoplasms metabolism, Uterine Cervical Neoplasms pathology, Xenograft Model Antitumor Assays, Carcinoma, Squamous Cell genetics, Cell Cycle Proteins genetics, Forkhead Box Protein M1 genetics, Forkhead Box Protein O3 genetics, Oncogene Proteins genetics, STAT3 Transcription Factor genetics, Uterine Cervical Neoplasms genetics
- Abstract
Uterine cervix cancer is the second most common malignancy in women worldwide with human papillomavirus (HPV) as the etiologic factor. The two main histological variants, squamous cell carcinomas (SCC) and adenocarcinomas (AC), resemble the cell morphology of exocervix and endocervix, respectively. Cancer metabolism is a cancer hallmark conditioned by the microenvironment. As uterine cervix homeostasis is dependent on lactate, we hypothesized lactate plays a role in uterine cervix cancer progression. Using in vitro (SiHa-SCC and HeLa-AC) and BALB-c/SCID models, we demonstrated that lactate metabolism is linked to histological types, with SCC predominantly consuming and AC producing lactate. MCT1 is a key factor, allowing lactate consumption and being regulated in vitro by lactate through the FOXM1:STAT3 pathway. In vivo models showed that SCC (SiHa) expresses MCT1 and is dependent on lactate to grow, whereas AC (HeLa) expresses MCT1 and MCT4, with higher growth capacities. Immunohistochemical analysis of tissue microarrays (TMA) from human cervical tumors showed that MCT1 expression associates with the SCC type and metastatic behavior of AC, whereas MCT4 expression concomitantly increases from in situ SCC to invasive SCC and is significantly associated with the AC type. Consistently, FOXM1 expression is statistically associated with MCT1 positivity in SCC, whereas the expression of FOXO3a, a FOXM1 functional antagonist, is linked to MCT1 negativity in AC. Our study reinforces the role of the microenvironment in the metabolic adaptation of cancer cells, showing that cells that retain metabolic features of their normal counterparts are positively selected by the organ's microenvironment and will survive. In particular, MCT1 was shown to be a key element in uterine cervix cancer development; however, further studies are needed to validate MCT1 as a suitable therapeutic target in uterine cervix cancer.
- Published
- 2016
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283. Thyroid Cancer Metabolism: A Review.
- Author
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Gill KS, Tassone P, Hamilton J, Hjelm N, Luginbuhl A, Cognetti D, Tuluc M, Martinez-Outschoorn U, Johnson JM, and Curry JM
- Abstract
Metabolic dysregulation within the tumor microenvironment (TME) is critical to the process of tumorigenesis in various cancer types. Thyrocyte metabolism in papillary and anaplastic thyroid cancer, however, remains poorly characterized, and studies analyzing the role of multicompartment metabolism in thyrocyte oncogenesis are sparse. We present a review of the current knowledge on cellular metabolism in non-cancerous and cancerous thyroid tissues, focusing on the monocarboxylate transporters MCT1 and MCT4, and on a transporter of the outer mitochondrial membrane TOMM20. Understanding the metabolic phenotype of tumor cells and associated stromal cells in thyroid cancer can have profound implications on the use of biomarker staining in detecting subclinical cancer, imaging as it relates to expression of various transport proteins, and therapeutic interventions that manipulate this dysregulated tumor metabolism to halt tumorigenesis and eradicate the cancer. Future studies are required to confirm the prognostic significance of these biomarkers and their correlation with existing staging schemas such as the AGES, AMES, ATA and MACIS scoring systems.
- Published
- 2016
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284. 3-bromopyruvate enhanced daunorubicin-induced cytotoxicity involved in monocarboxylate transporter 1 in breast cancer cells.
- Author
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Liu Z, Sun Y, Hong H, Zhao S, Zou X, Ma R, Jiang C, Wang Z, Li H, and Liu H
- Abstract
Increasing evidence demonstrates that the hexokinase inhibitor 3-bromopyruvate (3-BrPA) induces the cell apoptotic death by inhibiting ATP generation in human cancer cells. Interestingly, some tumor cell lines are less sensitive to 3-BrPA-induced apoptosis than others. Moreover, the molecular mechanism of 3-BrPA-trigged apoptosis is unclear. In the present study, we examined the effects of 3-BrPA on the viability of the breast cancer cell lines MDA-MB-231 and MCF-7. We further investigated the potential roles of monocarboxylate transporter 1 (MCT1) in drug accumulation and efflux of breast cancer cells. Finally, we explored whether 3-BrPA enhanced daunorubicin (DNR)-induced cytotoxicity through regulation of MCT1 in breast cancer cells. MTT and colony formation assays were used to measure cell viability. Western blot analysis, flow cytometric analysis and fluorescent microscopy were used to determine the molecular mechanism of actions of MCT1 in different breast cancer cell lines. Whole-body bioluminescence imaging was used to investigate the effect of 3-BrPA in vivo. We found that 3-BrPA significantly inhibited cell growth and induced apoptosis in MCF-7 cell line, but not in MDA-MB-231 cells. Moreover, we observed that 3-BrPA efficiently enhanced DNR-induced cytotoxicity in MCF-7 cells by inhibiting the activity of ATP-dependent efflux pumps. We also found that MCT1 overexpression increased the efficacy of 3-BrPA in MDA-MB-231 cells. 3-BrPA markedly suppressed subcutaneous tumor growth in combination with DNR in nude mice implanted with MCF-7 cells. Lastly, our whole-body bioluminescence imaging data indicated that 3-BrPA promoted DNR accumulation in tumors. These findings collectively suggest that 3-BrPA enhanced DNR antitumor activity in breast cancer cells involved MCT-1, suggesting that inhibition of glycolysis could be an effective therapeutic approach for breast cancer treatment.
- Published
- 2015
285. MCT1 promotes the cisplatin-resistance by antagonizing Fas in epithelial ovarian cancer.
- Author
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Yan C, Yang F, Zhou C, Chen X, Han X, Liu X, Ma H, and Zheng W
- Subjects
- Animals, Carcinoma, Ovarian Epithelial, Caspase 3 metabolism, Cell Line, Tumor, Cell Survival drug effects, Dose-Response Relationship, Drug, Fas Ligand Protein metabolism, Female, Gene Expression Regulation, Neoplastic, Humans, Mice, Inbred BALB C, Mice, Nude, Monocarboxylic Acid Transporters genetics, Neoplasms, Glandular and Epithelial genetics, Neoplasms, Glandular and Epithelial metabolism, Neoplasms, Glandular and Epithelial pathology, Ovarian Neoplasms genetics, Ovarian Neoplasms metabolism, Ovarian Neoplasms pathology, Protein Binding, Protein Tyrosine Phosphatase, Non-Receptor Type 13 metabolism, RNA Interference, Signal Transduction drug effects, Symporters genetics, Time Factors, Transfection, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Cisplatin pharmacology, Drug Resistance, Neoplasm genetics, Monocarboxylic Acid Transporters metabolism, Neoplasms, Glandular and Epithelial drug therapy, Ovarian Neoplasms drug therapy, Symporters metabolism, fas Receptor metabolism
- Abstract
This study was designed to investigate the role of MCT1 in the development of cisplatin-resistant ovarian cancer and its possible relationship with Fas. We found the expression of MCT1 was obviously increased both in cisplatin-resistant ovarian cancer tissue and A2780/CP cells compared with sensitive ovarian cancer tissue and cell lines A2780. And in A2780 cells treated with Cisplatin, the expression of MCT1 increased in a concentration-dependent manner, MCT1 knockdown attenuates cisplatin-induced cell viability. In A2780 and A2780/CP cells transfected with MCT1 siRNA, the activation of several downstream targets of Fas, including FasL and FAP-1 were largely prevented, whereas the expression of Caspase-3 was increased, accompanying with increased abundance of Fas. Coimmunoprecipitation and immunofluorescence showed that there is interaction between endogenous MCT1 with Fas in vivo and in vitro. In vivo, depletion of MCT1 by shRNA reverses cisplatin-resistance and the expression of Fas. This study showed that down regulation of MCT1 promote the sensibility to Cisplatin in ovarian cancer cell line. And this effect appeared to be mediated via antagonizing the effect of Fas.
- Published
- 2015
286. The influence of aging and cardiovascular training status upon monocarboxylate transporters
- Author
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Richards, William
- Subjects
- Monocarboxylate Transporter, MCT1, MCT4, Aging, Exercise
- Abstract
Isoforms of the lactate transporter known as monocarboxylate transporter (MCT) are increased in skeletal muscle following vigorous exercise. To date, no studies have investigated how age influences the content of MCT1 and MCT4 in human skeletal muscle. Purpose: To test the hypothesis that compared with the vastus lateralis (VL) of untrained subjects, the VL of endurance trained athletes would exhibit an increase in the content of MCT1 and MCT4. Methods: Healthy male subjects (n=33) were recruited and assigned to one of six groups based on age and training status (young trained (YT), n=6, 23.2 ± 0.8 yr, young untrained (YUT), n=6, 22.3 ± 2.9 yr, middle-aged trained (MAT), n=6, 46.3 ± 4.3 yr, middle-aged untrained (MAUT), n=5, 44.6 ± 3.9 yr, senior trained (ST) n=6, 58.7 ± 3.4 yr, and senior untrained (SUT), n=4, 58.8 ± 1.9 yr. The inclusion criteria required that all trained subjects spend at least 8 hours per week training above 60% of their VO2max, and that all untrained subjects have a self-reported average of less than 3 hours per week of moderate physical activity. Assignment to training status was supported by the completion of a VO2max test, by the wearing of an Actiheart downloadable heart rate monitor to record daily heart rates, and by completing a physical activity questionnaire. Muscle biopsies of the VL were analyzed via Western Blot for MCT1 and MCT4 content. Results: There were no significant age-related differences in MCT1 or MCT4 content (Y vs. MA vs. S, P > 0.05), and no significant differences in MCT1 or MCT4 content related to training status were observed (T vs. UT, P > 0.05). Conclusion: The results of this first study investigating an effect of age and training status on monocarboxylate transporters in human skeletal muscle suggests that age does not influence the level of the lactate transporter proteins MCT1 and MCT4.
- Published
- 2005
287. CD147 required for corneal endothelial lactate transport.
- Author
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Li S, Nguyen TT, and Bonanno JA
- Subjects
- Animals, Anterior Chamber metabolism, Blotting, Western, Carbonic Anhydrase Inhibitors pharmacology, Corneal Stroma metabolism, Fluorescent Antibody Technique, Indirect, Gene Silencing physiology, Hydrogen-Ion Concentration, Ion Transport, RNA, Small Interfering genetics, Rabbits, Real-Time Polymerase Chain Reaction, Sulfonamides pharmacology, Thiazines pharmacology, Transfection, Basigin physiology, Endothelium, Corneal metabolism, Lactic Acid metabolism, Monocarboxylic Acid Transporters metabolism
- Abstract
Purpose: CD147/basigin is a chaperone for lactate:H(+) cotransporters (monocarboxylate transporters) MCT1 and MCT4. We tested the hypothesis that MCT1 and -4 in corneal endothelium contribute to lactate efflux from stroma to anterior chamber and that silencing CD147 expression would cause corneal edema., Methods: CD147 was silenced via small interfering ribonucleic acid (siRNA) transfection of rabbit corneas ex vivo and anterior chamber lenti-small hairpin RNA (shRNA) pseudovirus in vivo. CD147 and MCT expression was examined by Western blot, RT-PCR, and immunofluorescence. Functional effects were examined by measuring lactate-induced cell acidification, corneal lactate efflux, [lactate], central cornea thickness (CCT), and Azopt (a carbonic anhydrase inhibitor) sensitivity., Results: In ex vivo corneas, 100 nM CD147 siRNA reduced CD147, MCT1, and MCT4 expression by 85%, 79%, and 73%, respectively, while MCT2 expression was unaffected. CD147 siRNA decreased lactate efflux from 3.9 ± 0.81 to 1.5 ± 0.37 nmol/min, increased corneal [lactate] from 19.28 ± 7.15 to 56.73 ± 8.97 nmol/mg, acidified endothelial cells (pHi = 6.83 ± 0.07 vs. 7.19 ± 0.09 in control), and slowed basolateral lactate-induced acidification from 0.0034 ± 0.0005 to 0.0012 ± 0.0005 pH/s, whereas apical acidification was unchanged. In vivo, CD147 shRNA increased CCT by 28.1 ± 0.9 μm at 28 days; Azopt increased CCT to 24.4 ± 3.12 vs. 12.0 ± 0.48 μm in control, and corneal [lactate] was 47.63 ± 6.29 nmol/mg in shCD147 corneas and 17.82 ± 4.93 nmol/mg in paired controls., Conclusions: CD147 is required for the expression of MCT1 and MCT4 in the corneal endothelium. Silencing CD147 slows lactate efflux, resulting in stromal lactate accumulation and corneal edema, consistent with lactate efflux as a significant component of the corneal endothelial pump., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)
- Published
- 2014
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288. Oxygen tension controls the expression of the monocarboxylate transporter MCT4 in cultured mouse cortical astrocytes via a hypoxia-inducible factor-1α-mediated transcriptional regulation.
- Author
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Rosafio K and Pellerin L
- Subjects
- Animals, Animals, Newborn, Cell Hypoxia physiology, Cells, Cultured, Enzyme Activation drug effects, Enzyme Inhibitors pharmacology, Glial Fibrillary Acidic Protein metabolism, Hypoglycemic Agents pharmacology, Lactic Acid metabolism, Mice, RNA, Small Interfering genetics, RNA, Small Interfering metabolism, Sodium Azide pharmacology, Transfection, Astrocytes drug effects, Cerebral Cortex cytology, Gene Expression Regulation drug effects, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Monocarboxylic Acid Transporters metabolism, Muscle Proteins metabolism, Oxygen pharmacology
- Abstract
The monocarboxylate transporter MCT4 is a high capacity carrier important for lactate release from highly glycolytic cells. In the central nervous system, MCT4 is predominantly expressed by astrocytes. Surprisingly, MCT4 expression in cultured astrocytes is low, suggesting that a physiological characteristic, not met in culture conditions, is necessary. Here we demonstrate that reducing oxygen concentration from 21% to either 1 or 0% restored in a concentration-dependent manner the expression of MCT4 at the mRNA and protein levels in cultured astrocytes. This effect was specific for MCT4 since the expression of MCT1, the other astrocytic monocarboxylate transporter present in vitro, was not altered in such conditions. MCT4 expression was shown to be controlled by the transcription factor hypoxia-inducible factor-1α (HIF-1α) since under low oxygen levels, transfecting astrocyte cultures with a siRNA targeting HIF-1α largely prevented MCT4 induction. Moreover, the prolyl hydroxylase inhibitor dimethyloxalylglycine (DMOG) induced MCT4 expression in astrocytes cultured in presence of 21% oxygen. In parallel, glycolytic activity was enhanced by exposure to 1% oxygen as demonstrated by the increased lactate release, an effect dependent on MCT4 expression. Finally, MCT4 expression was found to be necessary for astrocyte survival when exposed for a prolonged period to 1% oxygen. These data suggest that a major determinant of astrocyte MCT4 expression in vivo is likely the oxygen tension. This could be relevant in areas of high neuronal activity and oxygen consumption, favouring astrocytic lactate supply to neurons. Moreover, it could also play an important role for neuronal recovery after an ischemic episode., (Copyright © 2013 Wiley Periodicals, Inc.)
- Published
- 2014
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289. CryomiRs: towards the identification of a cold-associated family of microRNAs.
- Author
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Lyons PJ, Lang-Ouellette D, and Morin P Jr
- Subjects
- Acclimatization physiology, Animals, Fatty Acids biosynthesis, Fatty Acids metabolism, Freezing, Gene Expression Regulation, Insecta physiology, MicroRNAs biosynthesis, MicroRNAs genetics, Protein Processing, Post-Translational, Cold Temperature, Hibernation physiology, MicroRNAs physiology
- Abstract
Hypometabolism is a strategy favored by many species to survive extreme environmental stresses such as low temperatures, lack of food sources or anoxic conditions. Mammalian hibernation and insect cold hardiness are well-documented examples of natural models utilizing metabolic rate depression when confronted with such conditions. A plethora of metabolic and molecular changes must occur in these species to regulate this process. A recently discovered family of short non-coding nucleic acids, the miRNAs, is rapidly emerging as a potential modulator of cold tolerance in different species. In this review, we present the current knowledge associated with physiological and biochemical adaptations at low temperatures. We further explore the cascade of miRNA biogenesis as well as miRNA target recognition and translational repression. Finally, we introduce miRNAs shown to be differentially regulated in selected species when confronted with low temperatures and discuss the potential transcript targets regulated by these "CryomiRs"., (© 2013.)
- Published
- 2013
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- View/download PDF
290. The methionine precursor DL-2-hydroxy-(4-methylthio)butanoic acid protects intestinal epithelial barrier function.
- Author
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Martín-Venegas R, Brufau MT, Guerrero-Zamora AM, Mercier Y, Geraert PA, and Ferrer R
- Subjects
- Caco-2 Cells, Cell Membrane Permeability drug effects, Humans, Hydrogen Peroxide toxicity, Intestines cytology, Isomerism, Methionine chemistry, Methionine metabolism, Oxidative Stress drug effects, Protective Agents chemistry, Epithelial Cells metabolism, Intestinal Mucosa metabolism, Methionine analogs & derivatives, Protective Agents metabolism
- Abstract
DL-2-hydroxy-(4-methylthio)butanoic acid (HMTBA) is a source of dietary methionine (Met) that is widely used in poultry nutrition. We have previously shown that HMTBA is preferentially diverted to the transsulfuration pathway, which gives antioxidant metabolites such as taurine and glutathione. Therefore, here we hypothesize that this Met source can protect epithelial barrier function in an in vitro model of intestinal inflammation of Caco-2 cells. The results show that HMTBA prevents the increase in paracellular permeability induced by H2O2 or tumour necrosis factor-α. This effect can be attributed to the increased production of taurine and reduced glutathione. Similar results were obtained for DL-Met, although the protective role of the amino acid was less pronounced than that of the hydroxy analogue. In conclusion, the diversion to the transsulfuration pathway means that this Met precursor is of greater value than previously thought, due to its capacity to improve intestinal homeostasis and the quality of poultry products destined for human consumption., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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291. Green tea phenolics inhibit butyrate-induced differentiation of colon cancer cells by interacting with monocarboxylate transporter 1.
- Author
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Sánchez-Tena S, Vizán P, Dudeja PK, Centelles JJ, and Cascante M
- Subjects
- Adenocarcinoma drug therapy, Adenocarcinoma metabolism, Adenocarcinoma pathology, Alkaline Phosphatase metabolism, Anticarcinogenic Agents pharmacology, Apoptosis drug effects, Blotting, Western, Cell Membrane drug effects, Cell Membrane metabolism, Cell Proliferation drug effects, Colonic Neoplasms metabolism, Colonic Neoplasms pathology, Histamine Antagonists pharmacology, Humans, Membrane Microdomains drug effects, Membrane Microdomains metabolism, Tumor Cells, Cultured, Butyric Acid pharmacology, Catechin analogs & derivatives, Catechin pharmacology, Cell Differentiation drug effects, Colonic Neoplasms drug therapy, Monocarboxylic Acid Transporters metabolism, Polyphenols pharmacology, Tea chemistry
- Abstract
Diet has a significant impact on colorectal cancer and both dietary fiber and plant-derived compounds have been independently shown to be inversely related to colon cancer risk. Butyrate (NaB), one of the principal products of dietary fiber fermentation, induces differentiation of colon cancer cell lines by inhibiting histone deacetylases (HDACs). On the other hand, (-)-epicatechin (EC) and (-)-epigallocatechin gallate (EGCG), two abundant phenolic compounds of green tea, have been shown to exhibit antitumoral properties. In this study we used colon cancer cell lines to study the cellular and molecular events that take place during co-treatment with NaB, EC and EGCG. We found that (i) polyphenols EC and EGCG fail to induce differentiation of colon adenocarcinoma cell lines; (ii) polyphenols EC and EGCG reduce NaB-induced differentiation; (iii) the effect of the polyphenols is specific for NaB, since differentiation induced by other agents, such as trichostatin A (TSA), was unaltered upon EC and EGCG treatment, and (iv) is independent of the HDAC inhibitory activity of NaB. Also, (v) polyphenols partially reduce cellular NaB; and (vi) on a molecular level, reduction of cellular NaB uptake by polyphenols is achieved by impairing the capacity of NaB to relocalize its own transporter (monocarboxylate transporter 1, MCT1) in the plasma membrane. Our findings suggest that beneficial effects of NaB on colorectal cancer may be reduced by green tea phenolic supplementation. This valuable information should be of assistance in choosing a rational design for more effective diet-driven therapeutic interventions in the prevention or treatment of colorectal cancer., (© 2013.)
- Published
- 2013
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292. MCT1 is a predictive marker for lenalidomide maintenance therapy in multiple myeloma
- Author
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Katja Weisel, Christof Scheid, Markus Schick, Uta Bertsch, Martina Emde, Martina Rudelius, Anja Seckinger, Jolanta Slawska, Hans Salwender, Hartmut Goldschmidt, Ruth Eichner, Ulrich Keller, Dirk Hose, Jacob Stroh, Florian Bassermann, Michael Heider, Hematology, and Basic (bio-) Medical Sciences
- Subjects
Oncology ,medicine.medical_specialty ,Cancer Research ,lenalidomide maintenance therapy ,MCT1 ,Predictive ,Bortezomib ,Maintenance therapy ,Internal medicine ,Gene expression ,Internal Medicine ,medicine ,Humans ,Lenalidomide ,Multiple myeloma ,marker ,Predictive marker ,business.industry ,Hematology ,medicine.disease ,Stimulus Report ,Thalidomide ,Gene expression profiling ,business ,Multiple Myeloma ,Biomarkers ,medicine.drug - Abstract
Key Points High gene expression levels of MCT1 are associated with reduced PFS and OS in MM with lenalidomide-based maintenance therapy.Overexpression of MCT1 impairs efficacy of lenalidomide in human myeloma cells in vitro and in vivo., Biomarkers that predict response to lenalidomide maintenance therapy in patients with multiple myeloma (MM) have remained elusive. We have shown that immunomodulatory drugs (IMiDs) exert anti-MM activity via destabilization of MCT1 and CD147. In this study, cell samples of 654 patients with MM who received lenalidomide (n = 455), thalidomide (n = 98), or bortezomib (n = 101) maintenance were assessed by gene expression profiling and RNA sequencing, followed by correlation of MCT1 and CD147 expression with data for progression-free survival (PFS) and overall survival (OS). Patients with high expression levels of MCT1 showed significantly reduced PFS (31.9 months vs 48.2 months in MCT1high vs MCT1low; P = .03) and OS (75.9 months vs not reached [NR] in MCT1high vs MCT1low; P = .001) in cases with lenalidomide maintenance, whereas MCT1 expression had no significant impact on PFS or OS in cases with bortezomib maintenance. We validated the predictive role of MCT1 for IMiD-based maintenance in an independent cohort of patients who received thalidomide (OS, 83.6 months vs NR in MCT1high vs MCT1low; P = .03). Functional validation showed that MCT1 overexpression in human MM cell lines significantly reduced the efficacy of lenalidomide, whereas no change was observed with bortezomib treatment, either in vitro or in a MM xenograft model. Our findings have established MCT1 expression as a predictive marker for response to lenalidomide-based maintenance in patients with MM.
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293. Optimisation of immunofluorescence methods to determine MCT1 and MCT4 expression in circulating tumour cells
- Author
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Stephen Kershaw, Caroline Dive, Jeffrey Cummings, Karen Morris, and Jonathan Tugwood
- Subjects
Monocarboxylic Acid Transporters ,Pathology ,medicine.medical_specialty ,Cancer Research ,Immunofluorescence ,Fluorescent Antibody Technique ,Muscle Proteins ,Antineoplastic Agents ,MCT4 ,Pyrimidinones ,Thiophenes ,MCT1 ,Flow cytometry ,Cell Line, Tumor ,Circulating tumour cells ,AZD3965 ,medicine ,Genetics ,Humans ,Optimisation ,Monocarboxylate transporters ,medicine.diagnostic_test ,biology ,Clinical Trials, Phase I as Topic ,Symporters ,business.industry ,Cancer ,medicine.disease ,Neoplastic Cells, Circulating ,Small Cell Lung Carcinoma ,Healthy Volunteers ,Blot ,Technical Advance ,Oncology ,Cell culture ,biology.protein ,Cancer research ,Antibody ,Stem cell ,business ,Biomarkers - Abstract
The monocarboxylate transporter-1 (MCT1) represents a novel target in rational anticancer drug design while AZD3965 was developed as an inhibitor of this transporter and is undergoing Phase I clinical trials ( http://www.clinicaltrials.gov/show/NCT01791595 ). We describe the optimisation of an immunofluorescence (IF) method for determination of MCT1 and MCT4 in circulating tumour cells (CTC) as potential prognostic and predictive biomarkers of AZD3965 in cancer patients. Antibody selectivity was investigated by western blotting (WB) in K562 and MDAMB231 cell lines acting as positive controls for MCT1 and MCT4 respectively and by flow cytometry also employing the control cell lines. Ability to detect MCT1 and MCT4 in CTC as a 4th channel marker utilising the Veridex™ CellSearch system was conducted in both human volunteer blood spiked with control cells and in samples collected from small cell lung cancer (SCLC) patients. Experimental conditions were established which yielded a 10-fold dynamic range (DR) for detection of MCT1 over MCT4 (antibody concentration 6.25 μg/mL; integration time 0.4 seconds) and a 5-fold DR of MCT4 over MCT 1 (8 μg/100 μL and 0.8 seconds). The IF method was sufficiently sensitive to detect both MCT1 and MCT4 in CTCs harvested from cancer patients. The first IF method has been developed and optimised for detection of MCT 1 and MCT4 in cancer patient CTC.
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