Genomes and Genes
monocarboxylic acid transporters
Summary: A family of proteins involved in the transport of monocarboxylic acids such as LACTIC ACID and PYRUVIC ACID across cellular membranes.
- Erlichman J, Hewitt A, Damon T, Hart M, Kurascz J, Li A, et al. Inhibition of monocarboxylate transporter 2 in the retrotrapezoid nucleus in rats: a test of the astrocyte-neuron lactate-shuttle hypothesis. J Neurosci. 2008;28:4888-96 pubmed publisher..Therefore, neurons seem to metabolize a combination of glucose and lactate (and other substances such as pyruvate) depending, in part, on the availability of each of these particular substrates. ..
- Kennedy K, Dewhirst M. Tumor metabolism of lactate: the influence and therapeutic potential for MCT and CD147 regulation. Future Oncol. 2010;6:127-48 pubmed publisher..The possibility of metabolic modification of the tumor microenvironment via regulation or manipulation of MCT1 and CD147 may prove to be promising avenues of therapeutic options. ..
- Visser W, Jansen J, Friesema E, Kester M, Mancilla E, Lundgren J, et al. Novel pathogenic mechanism suggested by ex vivo analysis of MCT8 (SLC16A2) mutations. Hum Mutat. 2009;30:29-38 pubmed publisher..If fibroblasts are representative of central neurons, abnormal brain development associated with MCT8 mutations may be the consequence of either decreased or increased intracellular T3 concentrations. ..
- Izumi H, Takahashi M, Uramoto H, Nakayama Y, Oyama T, Wang K, et al. Monocarboxylate transporters 1 and 4 are involved in the invasion activity of human lung cancer cells. Cancer Sci. 2011;102:1007-13 pubmed publisher..This is the first report suggesting that lactate transporters are involved in human cancer cell invasiveness. As such, these proteins may be promising targets for the prevention of cancer invasion and metastasis. ..
- Halestrap A, Wilson M. The monocarboxylate transporter family--role and regulation. IUBMB Life. 2012;64:109-19 pubmed publisher..The recent discovery of potent and specific MCT1 inhibitors that prevent proliferation of T-lymphocytes confirms that MCTs may be promising pharmacological targets including for cancer chemotherapy. ..
- Sonveaux P, Vegran F, Schroeder T, Wergin M, Verrax J, Rabbani Z, et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest. 2008;118:3930-42 pubmed publisher..As MCT1 was found to be expressed by an array of primary human tumors, we suggest that MCT1 inhibition has clinical antitumor potential. ..
- Finch N, Linser P, Ochrietor J. Hydrophobic interactions stabilize the basigin-MCT1 complex. Protein J. 2009;28:362-8 pubmed publisher..The previously proposed hypothesis is partially correct, in that the putative transmembrane domain of Basigin does interact with MCT1. ..
- Friesema E, Jansen J, Jachtenberg J, Visser W, Kester M, Visser T. Effective cellular uptake and efflux of thyroid hormone by human monocarboxylate transporter 10. Mol Endocrinol. 2008;22:1357-69 pubmed publisher..hMCT10 was less active toward T(4) than hMCT8. These findings establish that hMCT10 is at least as active a thyroid hormone transporter as hMCT8, and that both transporters facilitate iodothyronine uptake as well as efflux. ..
- Sotgia F, Whitaker Menezes D, Martinez Outschoorn U, Flomenberg N, Birbe R, Witkiewicz A, et al. Mitochondrial metabolism in cancer metastasis: visualizing tumor cell mitochondria and the "reverse Warburg effect" in positive lymph node tissue. Cell Cycle. 2012;11:1445-54 pubmed publisher..Finally, MCT4(+) and TO MM20(-) "glycolytic" cancer cells were rarely observed, indicating that the conventional "Warburg effect" does not frequently occur in cancer-positive lymph node metastases. ..
- Pinheiro C, Longatto Filho A, Azevedo Silva J, Casal M, Schmitt F, Baltazar F. Role of monocarboxylate transporters in human cancers: state of the art. J Bioenerg Biomembr. 2012;44:127-39 pubmed publisher..Additional studies on MCT expression in other tumor types, confirmation of the results already published as well as additional functional studies are needed to deeply understand the role of MCTs in cancer maintenance and aggressiveness. ..
- Hao J, Chen H, Madigan M, Cozzi P, Beretov J, Xiao W, et al. Co-expression of CD147 (EMMPRIN), CD44v3-10, MDR1 and monocarboxylate transporters is associated with prostate cancer drug resistance and progression. Br J Cancer. 2010;103:1008-18 pubmed publisher..Expression of both CD147 and CD44v3-10 is correlated with drug resistance during CaP metastasis and could be a useful potential therapeutic target in advanced disease. ..
- Kinne A, Kleinau G, Hoefig C, Gruters A, Köhrle J, Krause G, et al. Essential molecular determinants for thyroid hormone transport and first structural implications for monocarboxylate transporter 8. J Biol Chem. 2010;285:28054-63 pubmed publisher..The MCT8 model allows us to rationalize potential interactions of amino acids including those mutated in patients with Allan-Herndon-Dudley syndrome. ..
- Thorrez L, Laudadio I, Van Deun K, Quintens R, Hendrickx N, Granvik M, et al. Tissue-specific disallowance of housekeeping genes: the other face of cell differentiation. Genome Res. 2011;21:95-105 pubmed publisher..Together, we provide a systematic analysis of tissue-specific repression of housekeeping genes, a phenomenon that has not been studied so far on a genome-wide basis and, when perturbed, can lead to human disease. ..
- Loubière L, Vasilopoulou E, Bulmer J, Taylor P, Stieger B, Verrey F, et al. Expression of thyroid hormone transporters in the human placenta and changes associated with intrauterine growth restriction. Placenta. 2010;31:295-304 pubmed publisher..Increased MCT8 and decreased MCT10 expression within placentae of pregnancies complicated by IUGR may contribute to aberrant development of the fetoplacental unit. ..
- Sickmann H, Walls A, Schousboe A, Bouman S, Waagepetersen H. Functional significance of brain glycogen in sustaining glutamatergic neurotransmission. J Neurochem. 2009;109 Suppl 1:80-6 pubmed publisher..Neurotransmitter release was affected by the presence of d-lactate indicating that glycogen derived energy is important not only in the astrocytic but also in the neuronal compartment...
- Queirós O, Preto A, Pacheco A, Pinheiro C, Azevedo Silva J, Moreira R, et al. Butyrate activates the monocarboxylate transporter MCT4 expression in breast cancer cells and enhances the antitumor activity of 3-bromopyruvate. J Bioenerg Biomembr. 2012;44:141-53 pubmed publisher..This study supports the potential use of butyrate as adjuvant of 3-BP in the treatment of breast cancer resistant cells, namely ER (-). ..
- Ganapathy V, Thangaraju M, Prasad P. Nutrient transporters in cancer: relevance to Warburg hypothesis and beyond. Pharmacol Ther. 2009;121:29-40 pubmed publisher..Since tumor cells selectively regulate these nutrient transporters to support their rapid growth, these transporters have potential as drug targets for cancer therapy. ..
- Filippi B, Alessi D. Novel role for the LKB1 pathway in controlling monocarboxylate fuel transporters. J Cell Biol. 2008;183:7-9 pubmed publisher..This enables cells to import additional energy sources such as lactate and butyrate, enhancing the repertoire of fuels they can use to power vital activities. ..
- Su J, Chen X, Kanekura T. A CD147-targeting siRNA inhibits the proliferation, invasiveness, and VEGF production of human malignant melanoma cells by down-regulating glycolysis. Cancer Lett. 2009;273:140-7 pubmed publisher..These results strongly suggest that highly-expressed CD147 interacts with MCT1 and 4 to promote tumor cell glycolysis, resulting in the progression of MM. ..
- Martinez Outschoorn U, Curry J, Ko Y, Lin Z, Tuluc M, Cognetti D, et al. Oncogenes and inflammation rewire host energy metabolism in the tumor microenvironment: RAS and NF?B target stromal MCT4. Cell Cycle. 2013;12:2580-97 pubmed publisher..Our results provide new support for the "seed and soil" hypothesis, which was first proposed in 1889 by the English surgeon, Stephen Paget. ..
- Pértega Gomes N, Vizcaíno J, Miranda Gonçalves V, Pinheiro C, Silva J, Pereira H, et al. Monocarboxylate transporter 4 (MCT4) and CD147 overexpression is associated with poor prognosis in prostate cancer. BMC Cancer. 2011;11:312 pubmed publisher..According to our results, we consider that MCT2 should be further explored as tumour marker and both MCT4 and CD147 as markers of poor prognosis in prostate cancer. ..
- Pinheiro C, Reis R, Ricardo S, Longatto Filho A, Schmitt F, Baltazar F. Expression of monocarboxylate transporters 1, 2, and 4 in human tumours and their association with CD147 and CD44. J Biomed Biotechnol. 2010;2010:427694 pubmed publisher..An important number of MCT1 positive cases are negative for both chaperones, suggesting that MCT plasma membrane expression in tumours may depend on a yet nonidentified regulatory protein. ..
- Hao J, Cozzi P, Khatri A, Power C, Li Y. CD147/EMMPRIN and CD44 are potential therapeutic targets for metastatic prostate cancer. Curr Cancer Drug Targets. 2010;10:287-306 pubmed..Additional focus will be on the potential of therapeutic strategies targeting CD147 and CD44 to prevent CaP metastasis and overcome drug resistance. ..
- Meredith D, Christian H. The SLC16 monocaboxylate transporter family. Xenobiotica. 2008;38:1072-106 pubmed
- Roberts L, Woodford K, Zhou M, Black D, Haggerty J, Tate E, et al. Expression of the thyroid hormone transporters monocarboxylate transporter-8 (SLC16A2) and organic ion transporter-14 (SLCO1C1) at the blood-brain barrier. Endocrinology. 2008;149:6251-61 pubmed publisher..The high microvessel expression of OATP14 in rodent compared with human brain may contribute to the relatively mild phenotype observed in Mct8-null mice, in contrast to humans lacking functional MCT8. ..
- Becker H, Deitmer J. Nonenzymatic proton handling by carbonic anhydrase II during H+-lactate cotransport via monocarboxylate transporter 1. J Biol Chem. 2008;283:21655-67 pubmed publisher..We present a hypothetical model in which the effective movement of H(+) into the bulk cytosol is increased by CAII, thus slowing the dissipation of the H(+) gradient across the cell membrane, which drives MCT1 activity. ..
- Morris M, Felmlee M. Overview of the proton-coupled MCT (SLC16A) family of transporters: characterization, function and role in the transport of the drug of abuse gamma-hydroxybutyric acid. AAPS J. 2008;10:311-21 pubmed publisher..Further studies are required to more clearly define the role of MCTs on drug disposition and the potential for MCT-mediated detoxification strategies in GHB overdose. ..
- Hashimoto T, Hussien R, Cho H, Kaufer D, Brooks G. Evidence for the mitochondrial lactate oxidation complex in rat neurons: demonstration of an essential component of brain lactate shuttles. PLoS ONE. 2008;3:e2915 pubmed publisher..These findings can be interpreted to mean that, as in skeletal muscle, neurons contain a mitochondrial lactate oxidation complex (mLOC) that has the potential to facilitate both intracellular and cell-cell lactate shuttles in brain. ..
- Semenza G. Tumor metabolism: cancer cells give and take lactate. J Clin Invest. 2008;118:3835-7 pubmed publisher..MCT1 expression was detected exclusively in nonhypoxic regions of human cancer biopsy samples, and in combination, these data suggest that MCT1 inhibition holds potential as a novel cancer therapy. ..
- Merezhinskaya N, Fishbein W. Monocarboxylate transporters: past, present, and future. Histol Histopathol. 2009;24:243-64 pubmed publisher..Along the way we posit questions or suggestions for future research. ..
- Kemp B, Church D, Hatzold J, Conradt B, Lambie E. Gem-1 encodes an SLC16 monocarboxylate transporter-related protein that functions in parallel to the gon-2 TRPM channel during gonad development in Caenorhabditis elegans. Genetics. 2009;181:581-91 pubmed publisher..GEM-1GFP is expressed within the gonadal precursor cells and localizes to the plasma membrane. Therefore, we propose that GEM-1 acts in parallel to the GON-2 channel to promote cation uptake within the developing gonad. ..
- Rae C, Nasrallah F, Broer S. Metabolic effects of blocking lactate transport in brain cortical tissue slices using an inhibitor specific to MCT1 and MCT2. Neurochem Res. 2009;34:1783-91 pubmed publisher..Further experiments investigating the mechanism of operation of AR-C122982 are necessary to corroborate this finding. ..
- Slomiany M, Grass G, Robertson A, Yang X, Maria B, Beeson C, et al. Hyaluronan, CD44, and emmprin regulate lactate efflux and membrane localization of monocarboxylate transporters in human breast carcinoma cells. Cancer Res. 2009;69:1293-301 pubmed publisher..Together, these data indicate that constitutive interactions among hyaluronan, CD44, and emmprin contribute to regulation of MCT localization and function in the plasma membrane of breast carcinoma cells. ..
- Vasilopoulou E, Loubière L, Martin Santos A, McCabe C, Franklyn J, Kilby M, et al. Differential triiodothyronine responsiveness and transport by human cytotrophoblasts from normal and growth-restricted pregnancies. J Clin Endocrinol Metab. 2010;95:4762-70 pubmed publisher..Increased monocarboxylate transporter 8 expression and intracellular T(3) accumulation may contribute to the altered T(3) responsiveness of IUGR cytotrophoblasts. ..
- Ngan A, Wang Y. Tissue-specific transcriptional regulation of monocarboxylate transporters (MCTs) during short-term hypoxia in zebrafish (Danio rerio). Comp Biochem Physiol B Biochem Mol Biol. 2009;154:396-405 pubmed publisher..This study has shown that fish utilize tissue-specific transcriptional regulation of MCTs along with other metabolic genes during hypoxia. ..
- Visser W, Friesema E, Visser T. Minireview: thyroid hormone transporters: the knowns and the unknowns. Mol Endocrinol. 2011;25:1-14 pubmed publisher..The prospects of identifying other transporters and transporter-based syndromes promise an exciting future in the TH transporter field. ..
- Ovens M, Manoharan C, Wilson M, Murray C, Halestrap A. The inhibition of monocarboxylate transporter 2 (MCT2) by AR-C155858 is modulated by the associated ancillary protein. Biochem J. 2010;431:217-25 pubmed publisher..The C-terminus of MCT2 was found to be essential for its expression with endogenous basigin. ..
- Heuer H, Visser T. Minireview: Pathophysiological importance of thyroid hormone transporters. Endocrinology. 2009;150:1078-83 pubmed publisher..It is expected that more specific thyroid hormone transporters will be discovered in the near future, which will lead to a better understanding of the tissue-specific regulation of thyroid hormone bioavailability. ..
- Whitaker Menezes D, Martinez Outschoorn U, Lin Z, Ertel A, Flomenberg N, Witkiewicz A, et al. Evidence for a stromal-epithelial "lactate shuttle" in human tumors: MCT4 is a marker of oxidative stress in cancer-associated fibroblasts. Cell Cycle. 2011;10:1772-83 pubmed..Most importantly, our current findings provide a new rationale and novel strategy for anti-cancer therapies, by employing MCT inhibitors. ..
- Martinez Outschoorn U, Balliet R, Lin Z, Whitaker Menezes D, Birbe R, Bombonati A, et al. BRCA1 mutations drive oxidative stress and glycolysis in the tumor microenvironment: implications for breast cancer prevention with antioxidant therapies. Cell Cycle. 2012;11:4402-13 pubmed publisher..In this regard, immunostaining with Cav-1 and MCT4 could be used as cost-effective biomarkers to monitor the response to antioxidant therapy. ..
- Suzuki A, Stern S, Bozdagi O, Huntley G, Walker R, Magistretti P, et al. Astrocyte-neuron lactate transport is required for long-term memory formation. Cell. 2011;144:810-23 pubmed publisher..We conclude that astrocyte-neuron lactate transport is required for long-term memory formation...
- Pinheiro C, Longatto Filho A, Simões K, Jacob C, Bresciani C, Zilberstein B, et al. The prognostic value of CD147/EMMPRIN is associated with monocarboxylate transporter 1 co-expression in gastric cancer. Eur J Cancer. 2009;45:2418-24 pubmed publisher..Our results showed that the prognostic value of CD147 was associated with MCT1 co-expression in gastric cancer cells, supporting the view that CD147 plasma membrane activity is dependent on MCT co-expression. ..
- Wilson M, Meredith D, Bunnun C, Sessions R, Halestrap A. Studies on the DIDS-binding site of monocarboxylate transporter 1 suggest a homology model of the open conformation and a plausible translocation cycle. J Biol Chem. 2009;284:20011-21 pubmed publisher..The cross-linking data have also been used to model a structure of MCT1 bound to embigin that is consistent with published data. ..
- Pérez de Heredia F, Wood I, Trayhurn P. Hypoxia stimulates lactate release and modulates monocarboxylate transporter (MCT1, MCT2, and MCT4) expression in human adipocytes. Pflugers Arch. 2010;459:509-18 pubmed publisher..Increased lactate production and monocarboxylate transporter expression are likely to be key components of the adaptive response of adipocytes to low O(2) tension as adipose tissue mass expands in obesity. ..
- Giatromanolaki A, Koukourakis M, Koutsopoulos A, Mendrinos S, Sivridis E. The metabolic interactions between tumor cells and tumor-associated stroma (TAS) in prostatic cancer. Cancer Biol Ther. 2012;13:1284-9 pubmed publisher..These findings support and extend our previous studies on energy recycling between the aerobic stroma and the anaerobic cancer cells within the framework of Warburg effect. ..
- Fiaschi T, Marini A, Giannoni E, Taddei M, Gandellini P, De Donatis A, et al. Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay. Cancer Res. 2012;72:5130-40 pubmed publisher..Hence, cancer cells allocate Warburg metabolism to their corrupted CAFs, exploiting their byproducts to grow in a low glucose environment, symbiotically adapting with stromal cells to glucose availability. ..
- Ovens M, Davies A, Wilson M, Murray C, Halestrap A. AR-C155858 is a potent inhibitor of monocarboxylate transporters MCT1 and MCT2 that binds to an intracellular site involving transmembrane helices 7-10. Biochem J. 2010;425:523-30 pubmed publisher..Biol. Chem. 284, 20011-20021]. ..
- Maekawa F, Minehira K, Kadomatsu K, Pellerin L. Basal and stimulated lactate fluxes in primary cultures of astrocytes are differentially controlled by distinct proteins. J Neurochem. 2008;107:789-98 pubmed publisher..In contrast, basigin appears to critically regulate the enhancement of lactate release caused by glutamate (or sodium azide) but via an effect on another unidentified transporter at least present in astrocytes in vitro. ..
- Halestrap A. The monocarboxylate transporter family--Structure and functional characterization. IUBMB Life. 2012;64:1-9 pubmed publisher..MCT1, MCT3, and MCT4 bind preferentially to basigin and MCT2 to embigin. The choice of binding partner does not affect substrate specificity or kinetics but can influence inhibitor specificity. ..
- Wirth E, Sheu S, Chiu Ugalde J, Sapin R, Klein M, Mossbrugger I, et al. Monocarboxylate transporter 8 deficiency: altered thyroid morphology and persistent high triiodothyronine/thyroxine ratio after thyroidectomy. Eur J Endocrinol. 2011;165:555-61 pubmed publisher..MCT8 contributes to hormone release from the thyroid gland...
- Rademakers S, Lok J, van der Kogel A, Bussink J, Kaanders J. Metabolic markers in relation to hypoxia; staining patterns and colocalization of pimonidazole, HIF-1?, CAIX, LDH-5, GLUT-1, MCT1 and MCT4. BMC Cancer. 2011;11:167 pubmed publisher..Colocalization and staining patterns of metabolic and hypoxia-related proteins provides valuable additional information over single protein analyses and can improve the understanding of their functions and environmental influences. ..
- Vegran F, Boidot R, Michiels C, Sonveaux P, Feron O. Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-?B/IL-8 pathway that drives tumor angiogenesis. Cancer Res. 2011;71:2550-60 pubmed publisher..In conclusion, our findings establish a signaling role for lactate in endothelial cells and they identify the lactate/NF-?B/IL-8 pathway as an important link between tumor metabolism and angiogenesis. ..
- Zhao Z, Wu M, Zou C, Tang Q, Lu J, Liu D, et al. Downregulation of MCT1 inhibits tumor growth, metastasis and enhances chemotherapeutic efficacy in osteosarcoma through regulation of the NF-?B pathway. Cancer Lett. 2014;342:150-8 pubmed publisher..In conclusion, our data, for the first time, demonstrate that MCT1 inhibition has antitumor potential which is associated with the NF-?B pathway, and high MCT1 expression predicates poor overall survival in patients with osteosarcoma. ..
- Martinez Outschoorn U, Lin Z, Whitaker Menezes D, Howell A, Lisanti M, Sotgia F. Ketone bodies and two-compartment tumor metabolism: stromal ketone production fuels mitochondrial biogenesis in epithelial cancer cells. Cell Cycle. 2012;11:3956-63 pubmed publisher..Furthermore, they suggest that we should target ketone body metabolism as a new area for drug discovery, for the prevention and treatment of human cancers. ..
- Friesema E, Visser W, Visser T. Genetics and phenomics of thyroid hormone transport by MCT8. Mol Cell Endocrinol. 2010;322:107-13 pubmed publisher..Therefore, the criterion for MCT8 mutation screening in these patients is the profile of increased T(3) and low-normal to low FT(4) serum levels. ..