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Lactate AND MCT4

Sina Ibne Noor, Jacques Pouyssegur, Joachim W Deitmer, Holger M Becker
Monocarboxylate transporters (MCTs) mediate the proton-coupled transport of high-energy metabolites like lactate and pyruvate and are expressed in nearly every mammalian tissue. We have shown previously that transport activity of MCT4 is enhanced by carbonic anhydrase II (CAII), which has been suggested to function as a 'proton antenna' for the transporter. In the present study we tested whether creation of an endogenous proton antenna by introduction of a cluster of histidine residues into the C-terminal tail of MCT4 (MCT4-6xHis) could facilitate MCT4 transport activity when heterologously expressed in Xenopus oocytes...
November 15, 2016: FEBS Journal
Riccardo Balzan, Laetitia Fernandes, Laetitia Pidial, Arnaud Comment, Bertrand Tavitian, Paul R Vasos
Pyruvate membrane crossing and its LDH-mediated conversion to lactate in cells featuring different levels of expression of membrane monocarboxylate transporters (MCT4) was probed using dissolution DNP-enhanced NMR. Hyperpolarized (13) C-1 labeled pyruvate was transferred to suspensions of rodent tumor cells CCL39. The pyruvate-to-lactate conversion rate monitored by dissolution-DNP NMR in CCL39 featuring native MCT4 expression level was lower than the rate observed for cells in which the human MCT4 gene was over-expressed...
November 12, 2016: Magnetic Resonance in Chemistry: MRC
Nigel P Moore, Catherine A Picut, Jeffrey H Charlap
The distribution of monocarboxylate transporter (MCT) isoforms 1 and 4, which mediate the plasmalemmal transport of l-lactic and pyruvic acids, has been identified in the placentae of rats and rabbits at different ages of gestation. Groups of three pregnant Sprague-Dawley rats and New Zealand White rabbits were sacrificed on gestation days (GD) 11, 14, 18, or 20 and on GD 13, 18, or 28, respectively. Placentae were removed and processed for immunohistochemical detection of MCT1 and MCT4. In the rat, staining for MCT1 was associated with lakes and blood vessels containing enucleated red blood cells (maternal vessels) while staining for MCT4 was associated with vessels containing nucleated red blood cells (embryofoetal vessels)...
2016: International Journal of Cell Biology
Cian McGinley, David John Bishop
This study measured the adaptive response to exercise training for each of the acid/base transport protein families, including providing isoform-specific evidence for the monocarboxylate transporter (MCT)1/4 chaperone protein basigin and for the electrogenic sodium/bicarbonate cotransporter (NBCe)1. We investigated whether 4 weeks of work-matched, high-intensity interval training (HIIT), performed either just above the lactate threshold (HIITΔ20; n = 8), or close to peak aerobic power (HIITΔ90; n = 8), influenced adaptations in acid/base transport protein abundance, non-bicarbonate muscle buffer capacity (βmin vitro), and exercise capacity in active men...
October 14, 2016: Journal of Applied Physiology
Luis V Portela, Andressa W Brochier, Clarissa B Haas, Afonso Kopczynski de Carvalho, Jussania A Gnoato, Eduardo R Zimmer, Eduardo Kalinine, Luc Pellerin, Alexandre P Muller
Hyperpalatable diets (HP) impair brain metabolism, and regular physical exercise has an apparent opposite effect. Here, we combined a prior long-term exposure to HP diet followed by physical exercise and evaluated the impact on some neuroenergetic components and on cognitive performance. We assessed the extracellular lactate concentration, expression of monocarboxylate transporters (MCTs), pyruvate dehydrogenase (PDH), and mitochondrial function in the hippocampus. Male C57BL/6J mice were fed 4 months with HP or a control diet...
September 22, 2016: Molecular Neurobiology
Erik S Knudsen, Uthra Balaji, Elizaveta Freinkman, Peter McCue, Agnieszka K Witkiewicz
Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. The aggressiveness and therapeutic recalcitrance of this malignancy has been attributed to multiple factors including the influence of an active desmoplastic stroma. How the stromal microenvironment of PDAC contributes to the fatal nature of this disease is not well defined. In the analysis of clinical specimens, we observed diverse expression of the hypoxic marker carbonic anhydrase IX and the lactate transporter MCT4 in the stromal compartment...
September 7, 2016: Oncotarget
Stefan Walenta, Nadine F Voelxen, Wolfgang Mueller-Klieser
The technique of induced metabolic bioluminescence imaging (imBI) has been developed to obtain a "snapshot" of the momentary metabolic status of biological tissues. Using cryosections of snap-frozen tissue specimens, imBI combines highly specific and sensitive in situ detection of metabolites with a spatial resolution on a microscopic level and with metabolic imaging in relation to tissue histology. Here, we present the application of imBI in human colorectal cancer. Comparing the metabolic information of one biopsy with that of 2 or 3 biopsies per individual cancer, the classification into high versus low lactate tumors, reflecting different glycolytic activities, based on a single biopsy was in agreement with the result from multiple biopsies in 83 % of all cases...
2016: Recent Results in Cancer Research
Anna Ferretta, Immacolata Maida, Stefania Guida, Amalia Azzariti, Letizia Porcelli, Stefania Tommasi, Paola Zanna, Tiziana Cocco, Michele Guida, Gabriella Guida
This study explores the (V600)BRAF-MITF-PGC-1α axis and compares metabolic and functional changes occurring in primary and metastatic (V600)BRAF melanoma cell lines. (V600)BRAF mutations in homo/heterozygosis were found to be correlated to high levels of pERK, to downregulate PGC-1α/β, MITF and tyrosinase activity, resulting in a reduced melanin synthesis as compared to BRAFwt melanoma cells. In this scenario, (V600)BRAF switches on a metabolic reprogramming in melanoma, leading to a decreased OXPHOS activity and increased glycolytic ATP, lactate, HIF-1α and MCT4 levels...
November 2016: Biochimica et Biophysica Acta
Kavindra Nath, Lili Guo, Bethany Nancolas, David S Nelson, Alexander A Shestov, Seung-Cheol Lee, Jeffrey Roman, Rong Zhou, Dennis B Leeper, Andrew P Halestrap, Ian A Blair, Jerry D Glickson
Lonidamine (LND) was initially introduced as an antispermatogenic agent. It was later found to have anticancer activity sensitizing tumors to chemo-, radio-, and photodynamic-therapy and hyperthermia. Although the mechanism of action remained unclear, LND treatment has been known to target metabolic pathways in cancer cells. It has been reported to alter the bioenergetics of tumor cells by inhibiting glycolysis and mitochondrial respiration, while indirect evidence suggested that it also inhibited l-lactic acid efflux from cells mediated by members of the proton-linked monocarboxylate transporter (MCT) family and also pyruvate uptake into the mitochondria by the mitochondrial pyruvate carrier (MPC)...
August 4, 2016: Biochimica et Biophysica Acta
Taiki Sato, Yu Kishimoto, Sanki Asakawa, Natsumi Mizuno, Masahiro Hiratsuka, Noriyasu Hirasawa
Many types of medical alloys include nickel (Ni), and the elution of Ni ions from these materials causes toxicities and inflammation. We have previously reported that inflammation enhances Ni elution, although the molecular mechanisms underlying this effect remain unclear. In this study, we investigated how inflammatory responses enhanced Ni elution in a wire-implantation mouse model. Subcutaneous implantation of Ni wire induced the expression of cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) mRNA in the surrounding tissues...
July 1, 2016: Toxicology
Myriam M Chaumeil, Marina Radoul, Chloé Najac, Pia Eriksson, Pavithra Viswanath, Michael D Blough, Charles Chesnelong, H Artee Luchman, J Gregory Cairncross, Sabrina M Ronen
Metabolic imaging of brain tumors using (13)C Magnetic Resonance Spectroscopy (MRS) of hyperpolarized [1-(13)C] pyruvate is a promising neuroimaging strategy which, after a decade of preclinical success in glioblastoma (GBM) models, is now entering clinical trials in multiple centers. Typically, the presence of GBM has been associated with elevated hyperpolarized [1-(13)C] lactate produced from [1-(13)C] pyruvate, and response to therapy has been associated with a drop in hyperpolarized [1-(13)C] lactate. However, to date, lower grade gliomas had not been investigated using this approach...
2016: NeuroImage: Clinical
Hugo Maciejewski, Muriel Bourdin, Léonard Féasson, Hervé Dubouchaud, Christian Denis, Hubert Freund, Laurent A Messonnier
The purpose of this study was to test if the lactate exchange (γ1) and removal (γ2) abilities during recovery following short all-out supramaximal exercise correlate with the muscle content of MCT1 and MCT4, the two isoforms of the monocarboxylate transporters family involved in lactate and H(+) co-transport in skeletal muscle. Eighteen lightweight rowers completed a 3-min all-out exercise on rowing ergometer. Blood lactate samples were collected during the subsequent passive recovery to assess an individual blood lactate curve (IBLC)...
2016: Frontiers in Physiology
Marco Johannes Battista, Kristina Goetze, Marcus Schmidt, Cristina Cotarelo, Veronika Weyer-Elberich, Annette Hasenburg, Wolfgang Mueller-Klieser, Stefan Walenta
PURPOSE: The precise determination of energy metabolites is challenged by the heterogeneity of their distribution, their rapid changes after surgical resection and the architectural complexity of malignancies. Induced metabolic bioluminescence imaging (imBI) allows to determine energy metabolites in tissue sections and to co-localize these with histological structures based on consecutive sections stained with HE. In this prospective pilot study patients with suspected advanced ovarian cancer (OC) were enrolled to prove the feasibility of imBI...
September 2016: Journal of Cancer Research and Clinical Oncology
Vera Miranda-Gonçalves, Sara Granja, Olga Martinho, Mrinalini Honavar, Marta Pojo, Bruno M Costa, Manuel M Pires, Célia Pinheiro, Michelle Cordeiro, Gil Bebiano, Paulo Costa, Rui M Reis, Fátima Baltazar
BACKGROUND: Glioblastomas (GBM) present a high cellular heterogeneity with conspicuous necrotic regions associated with hypoxia, which is related to tumor aggressiveness. GBM tumors exhibit high glycolytic metabolism with increased lactate production that is extruded to the tumor microenvironment through monocarboxylate transporters (MCTs). While hypoxia-mediated regulation of MCT4 has been characterized, the role of MCT1 is still controversial. Thus, we aimed to understand the role of hypoxia in the regulation of MCT expression and function in GBM, MCT1 in particular...
June 16, 2016: Oncotarget
Shotaro Sasaki, Yuya Futagi, Masaya Ideno, Masaki Kobayashi, Katsuya Narumi, Ayako Furugen, Ken Iseki
In the present study, we demonstrated that monocarboxylate transporter 4 (MCT4) is functionally expressed in Caco-2 cells. We studied the effects of 4 nonsteroidal anti-inflammatory drugs on the uptake of l-lactate as a good substrate of MCT4 by the cells. The monocarboxylate drugs inhibited the uptake of l-lactate into the cells. Diclofenac, as a member of the aryl-acetic acid group of nonsteroidal anti-inflammatory drugs, was the most potent inhibitor, with an inhibition constant of 20 μM. In the next study, we determined the type of inhibition for diclofenac...
June 2016: Drug Metabolism and Pharmacokinetics
Susana Simões-Sousa, Sara Granja, Céline Pinheiro, Daniela Fernandes, Adhemar Longatto-Filho, Ana Carolina Laus, Cira Danielle Casado Alves, J M Suárez-Peñaranda, Mario Pérez-Sayáns, Andre Lopes Carvalho, Fernando C Schmitt, Abel García-García, Fatima Baltazar
BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common type of cancer. The majority of patients present advanced stage disease and has poor survival. Therefore, it is imperative to search for new biomarkers and new alternative and effective treatment options. Most cancer cells rely on aerobic glycolysis to generate energy and metabolic intermediates. This phenotype is a hallmark of cancer, characterized by an increase in glucose consumption and production of high amounts of lactate...
July 17, 2016: Cell Cycle
Ji Yun Lee, InKyoung Lee, Won Jin Chang, Su Min Ahn, Sung Hee Lim, Hae Su Kim, Kwai Han Yoo, Ki Sun Jung, Haa-Na Song, Jin Hyun Cho, Sun Young Kim, Kyoung-Mee Kim, Soojin Lee, Seung Tae Kim, Se Hoon Park, Jeeyun Lee, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Won Ki Kang
Monocarboxylate transporters (MCTs) play a major role in up-regulation of glycolysis and adaptation to acidosis. However, the role of MCTs in gastric cancer (GC) is not fully understood. We investigated the potential utilization of a new cancer therapy for GC. We characterized the expression patterns of the MCT isoforms 1, 2, and 4 and investigated the role of MCT in GC through in vitro and in vivo tests using siRNA targeting MCTs. In GC cell lines, MCT1, 2, and 4 were up-regulated with different expression levels; MCT1 and MCT4 were more widely expressed in GC cell lines compared with MCT2...
May 20, 2016: Oncotarget
Thulasiraman Parkunan, Bikash Chandra Das, Arun Kumar Das, Dipak Banerjee, Niharika Mohanty, Avishek Paul, P K Nanda, T K Biswas, S Naskar, Sadhan Bag, Mihir Sarkar, N H Mohan
Present study explores the effect of hot summer period on the glycolytic rate at an early post-mortem meat quality of Ghungroo and Large White Yorkshire (LWY) pig and the comparative adaptability to high temperature between above breeds by shifting the expression of stress related genes like monocarboxylate transporters (MCTs) and heat shock proteins (HSPs). It was found that LWY exhibited significantly (p<0.01) higher plasma cortisol and lactate dehydrogenase (LDH) concentration than Ghungroo indicating their higher sensitivity to high temperature...
May 22, 2016: Asian-Australasian Journal of Animal Sciences
S S Messeha, N O Zarmouh, E Taka, S G Gendy, G R Shokry, M G Kolta, K F A Soliman
AIMS: In the presence of oxygen, most of the synthesized pyruvate during glycolysis in the cancer cell of solid tumors is released away from the mitochondria to form lactate (Warburg Effect). To maintain cell homeostasis, lactate is transported across the cell membrane by monocarboxylate transporters (MCTs). The major aim of the current investigation is to identify novel compounds that inhibit lactate efflux that may lead to identifying effective targets for cancer treatment. STUDY DESIGN: In this study, 900 ethanol plant extracts were screened for their lactate efflux inhibition using neuroblastoma (N2-A) cell line...
2016: European Journal of Medicinal Plants
Pavithra Viswanath, Chloe Najac, Jose L Izquierdo-Garcia, Aleksandr Pankov, Chibo Hong, Pia Eriksson, Joseph F Costello, Russell O Pieper, Sabrina M Ronen
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)...
June 7, 2016: Oncotarget
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