Monocarboxylate transporter 2 and stroke severity in a. The monocarboxylate transporter familystructure and functional characterization andrew p. Monocarboxylate transporters mct tocris bioscience. The monocarboxylate transporter familyrole and regulation andrew p. There are four isoforms, mcts 14, which are known to perform this function in mammals, each with distinct substrate and inhibitor affinities. Monocarboxylate transporter 1 is a protein that in humans is encoded by the slc16a1 gene also known as mct1. Monocarboxylate transporter 1 deficiency and ketone. Monocarboxylate transporter 1 mediates dl2hydroxy4. The monocarboxylate transporter familystructure and. In conclusion, mct4 is a highaffinity lactate transporter with physiologically relevant affinity for pyruvate. Monocarboxylate transporters mct catalyze the bidirectional protonlinked transport of shortchain monocarboxylates such as llactate, ketone bodies and pyruvate across the plasma membrane of mammalian cells. The role of mcts in cell homeostasis has been characterized in detail in normal tissues, however, their role in cancer is. Monocarboxylate transporters mcts catalyze the protonlinked transport of monocarboxylates such as llactate, pyruvate, and the ketone bodies across the plasma membrane.
The aim of the present work was to evaluate the clinicopathological value of monocarboxylate transporters mcts expression, namely mct1. Mct2 is a protoncoupled monocarboxylate transporter. It is a proton coupled monocarboxylate transporter. Renal cancer cells 786o and human vascular endothelial. It catalyzes the rapid transport across the plasma membrane of many monocarboxylates such as lactate, branchedchain oxo acids derived from. This study investigated the role of mct4 in oral squamous cell carcinoma oscc, and found that it is highly expressed in. In the intact rumen epithelium, isoforms 1 and 4 of the monocarboxylate transporter mct1 and mct4 are thought to play key roles in mediating transcellular and intracellular permeation of shortchain fatty acids and their metabolites and in maintaining intracellular ph. Monocarboxylate transporter mct 4, a phregulating protein, plays an important role in ph homeostasis of the glycolytic metabolic pathways in cancer cells. Recent work has shown that lactate efflux is mediated by monocarboxylate transporters mct, which are composed of a catalytic unit mct and an accessory subunit cd147, comprising the functional lactate transporter. Inhibition of monocarboxylate transporter4 depletes stem. Mutations in mct8 or slc16a2 lead to a severe form of xlinked psychomotor retardation, which is characterised by elevated plasma triiodothyronine t 3 and lownormal thyroxine t 4. Home cell metabolism modulators monocarboxylate transporter 1 mct 1 inhibitor. Monocarboxylate transporters mcts are membrane proteins acting as carriers for lactate, pyruvate, and ketone bodies.
Differential regulation of monocarboxylate transporter 8 expression. Monocarboxylate transporter 1 mct1 is an important determinant of the renal transport of the drug of abuse. Basigin cd147 is the target for organomercurial inhibition of monocarboxylate transporter isoforms 1 and 4. Pinedamfernandezetorrentsdestevezrlopezccampsmlloberasjzorzanoapalacin.
Mct1 4 are key in the regulation of many cellular processes. Characterisation of human monocarboxylate transporter 4. Role of monocarboxylate transporters in human cancers. In the present study, we analysed mct1, mct2, and mct4 protein expression in breast, colon, lung, and ovary neoplasms, as well as cd147 and cd44. Porporato1,2, and pierre sonveaux1 abstract extracellular acidosis resulting from intense metabolic activi. Monocarboxylate transporter 4 mct4 is a membrane transporter of monocarboxylates that has been reported to play an important role in tumorigenesis and progression in several solid tumor types. Clinical and functional relevance of the monocarboxylate. Mct14 are key in the regulation of many cellular processes. The present study aimed to investigate its clinical significance in esophageal squamous cell carcinoma escc. The warburg effect demonstrates the importance of glycolysis in the development of primary and metastatic cancers.
The importance of mcts is becoming increasingly evident as their extensive physiological and pathological roles are. Monocarboxylate transporter mct isoforms 14 catalyze the. Mct4 monocarboxylate transporter 4 slc16a3 c show summary. The protoncoupled monocarboxylate transporters monocarboxylate transporters 1, 4, 2 and 3 allow transport of the products of cellular metabolism, principally. Dids crosslinks mct1 to cd147 but not cd2 in rbl cells. Cancer cells drive tumour growth through aerobic glycolysis and must export lactate to maintain. In the south of france, former specialops mercenary frank. Monocarboxylate transporters mcts are important cellular ph regulators in cancer cells. Monocarboxylate transporter 4 facilitates cell proliferation and. We asked whether expression of the monocarboxylate transporter 8 mct8 and the. Abstract in the intact rumen epithelium, isoforms 1 and 4 of the monocarboxylate transporter mct1 and mct4 are thought to play key roles in mediating transcellular and intracellular permeation of shortchain fatty acids and their metabolites and in maintaining intracellular ph.
In particular, the slc16 family that encodes for the 14 isoforms of the monocarboxylate transporter mct family plays a significant role in the absorption, tissue distribution, and clearance of both endogenous and exogenous compounds. With ed skrein, loan chabanol, ray stevenson, lenn kudrjawizki. Aberrant expression of monocarboxylate transporter 4 in. The monocarboxylate transporter familyrole and regulation. Monocarboxylate transporter 2 and stroke severity in a rodent model of sleep apnea. View and buy high purity monocarboxylate transporter inhibitors from tocris bioscience.
The solute carrier slc slc16 gene family comprises 14 members and encodes for monocarboxylate transporters mcts. Mct1, mct3, and mct4 bind preferentially to basigin and mct2 to embigin. Augmented glycolysis not only takes place during hypoxia but also occurs under aerobic conditions 10, 21. Monocarboxylate transporters 1 and 4 are involved in the. Expression of monocarboxylate transporters 1, 2, and 4 in. Here we report the characterisation of mct4 expressed in xenopus oocytes. Slc16a3 monocarboxylate transporter 4 homo sapiens. Monocarboxylate transporter 4 ipr030756 interpro entry interpro. Monocarboxylate transporter 4 regulates maturation and. Lat2 is expressed in many tissues including the thyroid gland 4. Among the 14 mammalian slc16 family members, mct14 were identified as l lactate. Thyroid hormone transport across the plasma membrane depends on transmembrane transport proteins, including monocarboxylate transporter 8 mct8.
Halestrap school of biochemistry, medical sciences building, university of bristol, bristol, uk summary monocarboxylate transporters mcts catalyze the protonlinked transport of monocarboxylates such as llactate, pyru. Background monocarboxylate transporter 4 mct4, encoded by slc16a3 gene, is responsible for exporting lactic acid into the extracellular microenvironment, and an. The immunogen shows no significant sequence homology with other mct. Aberrant expression of monocarboxylate transporter 4 in tumour cells predicts an unfavourable outcome in patients with hepatocellular carcinoma. I originally wrote this paper for my biological systems class, the instructor of which was interested in researching the physiological role of monocarboxylate transporter 1 mct1. Whilst early stage disease is generally cured by surgery, advanced ec has a poor prognosis with limited treatment options. The monocarboxylate transporter 1 mct1 inhibitor, azd3965, is undergoing phase i evaluation in the united kingdom. Identifiers, dxs128, dxs128e, mct 7, mct 8, mct7, mct8, mrx22, xpct, ahds, solute carrier family 16 member 2. Monocarboxylate transporter 2 mct2 also known as solute carrier family 16 member 7 slc16a7 is a protein that in humans is encoded by the slc16a7 gene.
Monocarboxylate transporter 4 mct4 is a high affinity transporter. The present study showed that gbm exposure to hypoxic conditions increased mct4 expression. Slc16a3 monocarboxylate transporter 4 rattus norvegicus rat. Monocarboxylate transporter 4, associated with the acidification of synovial fluid, is a novel therapeutic target for inflammatory arthritis authors wataru fujii. Slc16 family of monocarboxylate transporters transporters. Disruption of the monocarboxylate transporter4basigin. Radecke 1, elisabeth wyart2, thibaut vazeille1, caroline bouzin3, paolo e.
In the heart and red skeletal muscle, mct1 is required for lactate and. Monocarboxylate transporter inhibitors tocris bioscience. Monocarboxylate transporter 4 mct4 is a cell membrane transporter of lactate. Prognostic value of monocarboxylate transporter 4 in. Lactate has long been considered a byproduct resulting from glucose breakdown through glycolysis during anaerobic metabolism.
Glioblastoma gbm is characterized by severe hypoxic and acidic stress in an abnormal microenvironment. Monocarboxylate transporter 4, associated with the. Monocarboxylate transporter 4 mct4 also known as solute carrier family 16 member 3 is a protein that in humans is encoded by the slc16a3 gene. Monocarboxylate transporter 4 mct4 and cd147 overexpression. Structure and function of a monocarboxylate transporter. Monocarboxylate transporter 4 mct4, also known as slc16a3, belongs to the mct family. Mct1mct4 are proton symporters, which mediate the transmembrane transport of pyruvate, lactate and ketone bodies. Inhibition of monocarboxylate transporter4 depletes stemlike glioblastoma cells and inhibits hif transcriptional response in a lactateindependent manner. Mct1d in their index patient, a girl of consanguineous syrian descent with recurrent, severe acidosis, van hasselt et al. Recognizes rat monocarboxylate transporter 4 mct4mot4 slc16a3. The uptake of valproic acid was not inhibited by shortchain less than c 4 fatty acids, but was significantly inhibited by mediumchain c 6 c 12 fatty acids, suggesting that the shortchain monocarboxylate transporter at the bbb is not involved in the luminal uptake of valproic acid. Monocarboxylate transporter 4 mct4 also known as solute carrier family 16 member 3 is a protein that in humans is encoded by the slc16a3 gene northern and western blotting and est database analyses showed mct4 to be widely expressed and especially so in glycolytic tissues such as white skeletal muscle fibers, astrocytes, white blood cells, chondrocytes, and some mammalian cell lines.
Wilson school of biochemistry, medical sciences building, university of bristol, bristol, uk summary monocarboxylate transporter mct isoforms 14 catalyze the protonlinked transport of monocarboxylates such as llac. Monocarboxylate transporter 4 mct4 also known as solute carrier family 16 member 3 is a protein that in humans is encoded by the slc16a3 gene northern and western blotting and est database analyses showed mct4 to be widely expressed and especially so in glycolytic tissues such as white skeletal muscle fibers, astrocytes, white blood cells, chondrocytes, and some. Under oxygen deprivation, most pyruvate is converted into lactate that is transported by the lactate transporter monocarboxylate transporter 4 mct4 2 outward to the extracellular environment 17 20. Monocarboxylate transporter mct isoforms 14 catalyze the proton. Journal of neuroscience july 2011, 31 28 1024110248. Monocarboxylate transporter 8 mct8 is an active transporter protein that in humans is encoded by the slc16a2 gene. Mcts are required for the transport of essential cell nutrients and for cellular metabolic and ph regulation. We aimed to explore the role of monocarboxylate transporter 1 mct1 and mct4, two essential transporters of lactate, in renal cancer progression during cancerendothelial cell coculturing. Ohno a1, yorita k, haruyama y, kondo k, kato a, ohtomo t, kawaguchi m, marutuska k, chijiiwa k, kataoka h.
Decreased astroglial monocarboxylate transporter 4. In the manuscript cancers673857 that is entitled monocarboxylate transporter 4 regulates glioblastoma motility and monocyte binding ability, the authors aimed at dissecting the biological functions of monocarboxylate transporter 4 mct4 in glioma cells under hypoxic coditions. Activity of the monocarboxylate transporter 1 inhibitor. Catalyzes the rapid transport across the plasma membrane of many monocarboxylates such as lactate, pyruvate. Clinical and functional relevance of the monocarboxylate transporter family in disease pathophysiology and drug therapy pascale fisel 1,2,elke schaeffeler and matthias schwab1,2,3,4,5. Altered energy metabolism is a hallmark of malignancy. Slc16a3 monocarboxylate transporter 4 homo sapiens human. Catalyzes the rapid transport across the plasma membrane of many monocarboxylates such as lactate, pyruvate, branchedchain oxo acids derived from leucine, valine and isoleucine, and the ketone bodies acetoacetate, betahydroxybutyrate and acetate by similarity.
Recent studies have shown that mct4 is overexpressed in various cancers. It is well known that cancer cells run high rate of glycolysis even when. Monocarboxylate transporter 1s facilitation of cancer. Monocarboxylate transporter an overview sciencedirect. Pdf monocarboxylate transporter 4 mct4 is a high affinity. By rachel hull, biochemistry and molecular biology, 19. Mct4 is prominently expressed in skeletal muscle and other cells with high glycolytic rate such as tumors cells and white blood cells suggesting an important role in lactic acid efflux. In addition, as described for cd147 and mct isoforms 1 and 4, there might be other chaperones involved in mct2 regulation. Monocarboxylate transporter mct1 promotes tumor metastasis independently of its activity as a lactate transporter valery l. Pdf evaluation of monocarboxylate transporter 4 in. We have previously shown that glioblastoma stem cells gscs are enriched in the hypoxic tumor microenvironment, and that monocarboxylate transporter4 mct4 is critical for mediating gsc. Monocarboxylate transporter 4 mct4 and cd147 overexpression is associated with poor prognosis in prostate cancer.
Antimonocarboxylate transporter 4 antibody sigmaaldrich. Mct4 and cd147 overexpression is associated with poor prognosis in prostate cancer. The protoncoupled monocarboxylate transporters monocarboxylate transporters 1, 4, 2 and 3 allow transport of the products of cellular metabolism, principally lactate e. Cd147 is tightly associated with lactate transporters mct1 and. Monocarboxylate transporter mct 4 is the major monocarboxylate transporter isoform present in white skeletal muscle and is responsible for the efflux of lactic acid produced by glycolysis. The role of monocarboxylate transporter 2 and 4 in the.
Azd3965 is proposed, via lactate transport modulation, to kill tumor cells reliant on glycolysis. Cancers free fulltext monocarboxylate transporter 4. Mct4 is one the key transporters involved in the regulation of. Monocarboxylate transporter an overview sciencedirect topics. Mct expression frequency was high and heterogeneous among. Monocarboxylate transporter mct 4 is the major monocarboxylate transporter isoform present in white skeletal muscle and is responsible for the efflux of lactic. Monocarboxylate transporters mcts belong to the slc16 gene family, presently composed by 14 members. Monocarboxylate transporters mcts are other important plasma membrane transporters that catalyze the protonlinked transport of monocarboxylates such as lactate and pyruvate, which play a major role in cell metabolism and metabolic communication between tissues. This result was surprising, however, since mct2 was not present in the plasma membrane, the mechanism of regulation might be different. Endometrial cancer ec is a major health concern due to its rising incidence. Themonocarboxylatetransporter4isrequiredforglycolytic. Monocarboxylate transporter 1 mct 1 inhibitor cell.
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