Showing papers on "Monocarboxylate transporter published in 2023"

Astrocytic lactate dehydrogenase A regulates neuronal excitability and depressive-like behaviors through lactate homeostasis in mice

Abstract: Abstract Alterations in energy metabolism are associated with depression. However, the role of glycolysis in the pathogenesis of depression and the underlying molecular mechanisms remain unexplored. Through an unbiased proteomic screen coupled with biochemical verifications, we show that the levels of glycolysis and lactate dehydrogenase A (LDHA), a glycolytic enzyme that catalyzes L-lactate production, are reduced in the dorsomedial prefrontal cortex (dmPFC) of stress-susceptible mice in chronic social defeat stress (CSDS) model. Conditional knockout of LDHA from the brain promotes depressive-like behaviors in both male and female mice, accompanied with reduced L-lactate levels and decreased neuronal excitability in the dmPFC. Moreover, these phenotypes could be duplicated by knockdown of LDHA in the dmPFC or specifically in astrocytes. In contrast, overexpression of LDHA reverses these phenotypic changes in CSDS-susceptible mice. Mechanistic studies demonstrate that L-lactate promotes neuronal excitability through monocarboxylic acid transporter 2 (MCT2) and by inhibiting large-conductance Ca 2+ -activated potassium (BK) channel. Together, these results reveal a role of LDHA in maintaining neuronal excitability to prevent depressive-like behaviors.

Thyroid Hormone Transporters MCT8 and OATP1C1 Are Expressed in Pyramidal Neurons and Interneurons in the Adult Motor Cortex of Human and Macaque Brain

Abstract: Monocarboxylate transporter 8 (MCT8) and organic anion transporter polypeptide 1C1 (OATP1C1) are thyroid hormone (TH) transmembrane transporters that play an important role in the availability of TH for neural cells, allowing their proper development and function. It is important to define which cortical cellular subpopulations express those transporters to explain why MCT8 and OATP1C1 deficiency in humans leads to dramatic alterations in the motor system. By means of immunohistochemistry and double/multiple labeling immunofluorescence in adult human and monkey motor cortices, we demonstrate the presence of both transporters in long-projection pyramidal neurons and in several types of short-projection GABAergic interneurons in both species, suggesting a critical position of these transporters for modulating the efferent motor system. MCT8 is present at the neurovascular unit, but OATP1C1 is only present in some of the large vessels. Both transporters are expressed in astrocytes. OATP1C1 was unexpectedly found, only in the human motor cortex, inside the Corpora amylacea complexes, aggregates linked to substance evacuation towards the subpial system. On the basis of our findings, we propose an etiopathogenic model that emphasizes these transporters’ role in controlling excitatory/inhibitory motor cortex circuits in order to understand some of the severe motor disturbances observed in TH transporter deficiency syndromes.

Prognostic Value of Monocarboxylate Transporter 1 Overexpression in Cancer: A Systematic Review

Abstract: Energy production by cancer is driven by accelerated glycolysis, independently of oxygen levels, which results in increased lactate production. Lactate is shuttled to and from cancer cells via monocarboxylate transporters (MCTs). MCT1 works both as an importer and an extruder of lactate, being widely studied in recent years and generally associated with a cancer aggressiveness phenotype. The aim of this systematic review was to assess the prognostic value of MCT1 immunoexpression in different malignancies. Study collection was performed by searching nine different databases (PubMed, EMBASE, ScienceDirect, Scopus, Cochrane Library, Web of Science, OVID, TRIP and PsycINFO), using the keywords “cancer”, “Monocarboxylate transporter 1”, “SLC16A1” and “prognosis”. Results showed that MCT1 is an indicator of poor prognosis and decreased survival for cancer patients in sixteen types of malignancies; associations between the transporter’s overexpression and larger tumour sizes, higher disease stage/grade and metastasis occurrence were also frequently observed. Yet, MCT1 overexpression correlated with better outcomes in colorectal cancer, pancreatic ductal adenocarcinoma and non-small cell lung cancer patients. These results support the applicability of MCT1 as a biomarker of prognosis, although larger cohorts would be necessary to validate the overall role of MCT1 as an outcome predictor.

Role and Clinical Significance of Monocarboxylate Transporter 8 (MCT8) During Pregnancy

Abstract: The review aims to summarize the available research focusing on the importance of monocarboxylate transporter (MCT8) in thyroid hormone trafficking across the placenta and fetal development. A systematic search was carried out in PubMed; studies available in English related to "monocarboxylate transporter", "adverse pregnancy", "fetal development," and "thyroid hormone" were identified and assessed. The references within the resulting articles were manually searched. MCT8 is a highly active and selective thyroid hormone transporter that facilitates the cellular uptake of triiodothyronine (T3), thyroxine (T4), reverse triiodothyronine (rT3), and diiodothyronine (T2) in different tissues. MCT8 is expressed in the placenta from the first trimester onwards, allowing the transport of thyroid hormone from mother to fetus. Mutations in MCT8 cause an X-linked disorder known as Allan-Herndon-Dudley syndrome (AHDS), characterized by severe psychomotor impairment and peripheral thyrotoxicosis. Hence, any maternal thyroid dysfunction may cause severe consequences for the fetus and newborn. Further research regarding MCT8 gene expression, polymorphic variation, and adverse pregnancy outcomes must be done to establish that MCT8 is a novel prognostic marker for the early detection of pregnancy-related complications.

Supplementary Figure Legend from Hyaluronan, CD44, and Emmprin Regulate Lactate Efflux and Membrane Localization of Monocarboxylate Transporters in Human Breast Carcinoma Cells

Abstract: Supplementary Figure Legend from Hyaluronan, CD44, and Emmprin Regulate Lactate Efflux and Membrane Localization of Monocarboxylate Transporters in Human Breast Carcinoma Cells

Supplementary Figure 2 from Glutamine Deprivation Enhances Antitumor Activity of 3-Bromopyruvate through the Stabilization of Monocarboxylate Transporter-1

Abstract: <p>PDF file - 147K, Autophagy contributes to the execution of 3-BrPA-induced cell death upon glutamine withdrawal</p>

Supplementary Table 1 from Inhibition of Monocarboxylate Transporter-1 (MCT1) by AZD3965 Enhances Radiosensitivity by Reducing Lactate Transport

Abstract: <p>This file contains details of the reaction conditions for determining glycolytic isoenzyme kinetics</p>

Supplementary Figure 4 from Glutamine Deprivation Enhances Antitumor Activity of 3-Bromopyruvate through the Stabilization of Monocarboxylate Transporter-1

Abstract: <p>PDF file - 55K, Increased oxidative stress underlies 3-BrPA chemo-potentiation induced by glutamine-deprivation</p>

Supplementary Figure 3 from Inhibition of Monocarboxylate Transporter-1 (MCT1) by AZD3965 Enhances Radiosensitivity by Reducing Lactate Transport

Abstract: <p>This file shows a comparison of the effect of hypoxia on metabolite profiles.</p>

Supplementary Figure 3 from Inhibition of Monocarboxylate Transporter-1 (MCT1) by AZD3965 Enhances Radiosensitivity by Reducing Lactate Transport

Abstract: <p>This file shows a comparison of the effect of hypoxia on metabolite profiles.</p>

Supplementary Methods from Preclinical Efficacy of the Novel Monocarboxylate Transporter 1 Inhibitor BAY-8002 and Associated Markers of Resistance

Abstract: <p>Supplementary Methods: Synthesis and characterization of BAY-8002; Tritium labeling of AZD3965 and BAY-8002; MCT1 and MCT4 14C-lactate uptake measurements in the X. laevis oocytes expression System</p>

Supplementary Figure 9 from Glutamine Deprivation Enhances Antitumor Activity of 3-Bromopyruvate through the Stabilization of Monocarboxylate Transporter-1

Abstract: <p>PDF file - 104K, Scheme of 3-BrPA chemo-potentiation induced by glutamine deprivation</p>

Supplementary Figure 3 from Glutamine Deprivation Enhances Antitumor Activity of 3-Bromopyruvate through the Stabilization of Monocarboxylate Transporter-1

Abstract: <p>PDF file - 154K, Glutamine deprivation-induced 3-BrPA chemo-potentiation does not depend on synergistic impairment of glutaminolysis and glycolysis</p>

Supplementary Figure 8 from Glutamine Deprivation Enhances Antitumor Activity of 3-Bromopyruvate through the Stabilization of Monocarboxylate Transporter-1

Abstract: <p>PDF file - 98K, Glutamine synthetase is exploited by cancer cells to circumvent 3-BrPA chemo-potentiation</p>

Effects of mobile phone electromagnetic radiation on thyroid glands and hormones in Rattus norvegicus brain: An analysis of thyroid function, reactive oxygen species, and monocarboxylate transporter 8

Abstract: The aim of this study was to investigate the effects of mobile phone electromagnetic radiation (MP-EMR) on the thyroid glands and hormones in Rattus norvegicus brain in term of thyroid function, reactive oxygen species (ROS), and monocarboxylate transporter 8 (MCT8) concentration. Forty rats were divided into different groups: control (without EMR exposure), EMR1 (120-min/day exposure), EMR2 (150-min), and EMR3 (180-min). The levels of serum thyroid stimulating hormone (TSH), thyroxine (T4), and malondialdehyde (MDA) and brain and MCT8 were measured using enzyme-linked immunosorbent assay. One-way analysis of variance followed by the Duncan test was used to analyze the data. Our data indicated that the levels of serum TSH and T4 in all the EMR groups were lower significant postexposure compared to the control with P < 0.01 (EMR1 and EMR2) and P < 0.001 (EMR3), suggesting hypothyroidism due to MP-EMR exposure. Increased MDA and decreased MCT8 levels were also observed following the intervention; however, the changes in both concentrations were notably significant after being subjected to 150-min and 180-min of exposure. In conclusion, a significant reduction in TSH, T4, and MCT8 levels indicated thyroid dysfunction due to MP-EMR exposure.

Supplementary Figure Legend from Hyaluronan, CD44, and Emmprin Regulate Lactate Efflux and Membrane Localization of Monocarboxylate Transporters in Human Breast Carcinoma Cells

Abstract: Supplementary Figure Legend from Hyaluronan, CD44, and Emmprin Regulate Lactate Efflux and Membrane Localization of Monocarboxylate Transporters in Human Breast Carcinoma Cells

Supplementary Figure 1 from Glutamine Deprivation Enhances Antitumor Activity of 3-Bromopyruvate through the Stabilization of Monocarboxylate Transporter-1

Abstract: <p>PDF file - 127K, Chemo-potentiation of 3-BrPA cytotoxicity is not associated with the activation of apoptosis</p>

Data from Monocarboxylate Transporter 4 Regulates Maturation and Trafficking of CD147 to the Plasma Membrane in the Metastatic Breast Cancer Cell Line MDA-MB-231

Abstract: <div>Abstract<p>Metastatic cancer cells increase glucose consumption and metabolism via glycolysis, producing large quantities of lactate. 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. CD147, an extracellular matrix metalloproteinase (MMP) inducer, is highly expressed in metastatic cancer cells. Because aerobic glycolysis is a hallmark of metastatic cancer, we examined whether increases in CD147 expression were linked to MCT expression in MDA-MB-231, a highly metastatic breast cancer cell line. MCT4 mRNA and protein expression were increased in MDA-MB-231 cells compared with cells derived from normal mammary tissue. MCT4 colocalized with CD147 in the plasma membrane and in membrane blebs shed from the cell surface. Small interfering RNA–mediated silencing of MCT4 impaired the maturation and trafficking of CD147 to the cell surface, resulting in accumulation of CD147 in the endoplasmic reticulum. Silencing MCT4 also resulted in fewer membrane blebs and decreased migration of MDA-MB-231 cells <i>in vitro</i>. Knockdown of CD147 resulted in loss of MCT4 in the plasma membrane and accumulation of the transporter in endolysosomes. These studies establish for the first time that increased expression of CD147 in metastatic cancer cells is coupled to the up-regulation of MCT4. The synergistic activities of the MCT/CD147 complex could facilitate migration of tumor cells by CD147-mediated MMP induction and lactate-stimulated angiogenesis and hyaluronan production. These data provide a molecular link between two hallmarks of metastatic cancer: the glycolytic switch and increased expression of CD147. [Cancer Res 2007;67(9):4182–9]</p></div>

Supplementary Figure 6 from Inhibition of Monocarboxylate Transporter-1 (MCT1) by AZD3965 Enhances Radiosensitivity by Reducing Lactate Transport

Abstract: <p>This file shows IHC slides of H526 tumors taken from mice treated with or without AZD3965 and stained for MCT4 or CD31 expression.</p>

Supplementary Figure Legends from Inhibition of Monocarboxylate Transporter-1 (MCT1) by AZD3965 Enhances Radiosensitivity by Reducing Lactate Transport

Abstract: <p>This file provides the legends to Supplementary figures 1-6.</p>

Supplementary Figure 7 from Glutamine Deprivation Enhances Antitumor Activity of 3-Bromopyruvate through the Stabilization of Monocarboxylate Transporter-1

Abstract: <p>PDF file - 180K, MCT-1 up-regulation induced by glutamine deprivation is responsible for 3-BrPA chemo-potentiation</p>

Supplementary Materials and Methods from Regulation of Monocarboxylate Transporter MCT1 Expression by p53 Mediates Inward and Outward Lactate Fluxes in Tumors

Abstract: <p>PDF file - 36K</p>

Supplementary Figure 2 from Inhibition of Monocarboxylate Transporter-1 (MCT1) by AZD3965 Enhances Radiosensitivity by Reducing Lactate Transport

Abstract: <p>This file shows a hierarchical analysis of individual metabolites</p>

Supplementary Methods from Lactate Influx through the Endothelial Cell Monocarboxylate Transporter MCT1 Supports an NF-κB/IL-8 Pathway that Drives Tumor Angiogenesis

Abstract: Supplementary Methods from Lactate Influx through the Endothelial Cell Monocarboxylate Transporter MCT1 Supports an NF-κB/IL-8 Pathway that Drives Tumor Angiogenesis

Supplementary Figure 5 from Inhibition of Monocarboxylate Transporter-1 (MCT1) by AZD3965 Enhances Radiosensitivity by Reducing Lactate Transport

Abstract: <p>This file shows the aerobic and anoxic toxicity of AZD3965.</p>

Data from Glutamine Deprivation Enhances Antitumor Activity of 3-Bromopyruvate through the Stabilization of Monocarboxylate Transporter-1

Abstract: <div>Abstract<p>Anticancer drug efficacy might be leveraged by strategies to target certain biochemical adaptations of tumors. Here we show how depriving cancer cells of glutamine can enhance the anticancer properties of 3-bromopyruvate, a halogenated analog of pyruvic acid. Glutamine deprival potentiated 3-bromopyruvate chemotherapy by increasing the stability of the monocarboxylate transporter-1, an effect that sensitized cells to metabolic oxidative stress and autophagic cell death. We further elucidated mechanisms through which resistance to chemopotentiation by glutamine deprival could be circumvented. Overall, our findings offer a preclinical proof-of-concept for how to employ 3-bromopyruvate or other monocarboxylic-based drugs to sensitize tumors to chemotherapy. <i>Cancer Res; 72(17); 4526–36. ©2012 AACR</i>.</p></div>

Data from Monocarboxylate Transporter MCT1 Promotes Tumor Metastasis Independently of Its Activity as a Lactate Transporter

Abstract: <div>Abstract<p>Extracellular acidosis resulting from intense metabolic activities in tumors promotes cancer cell migration, invasion, and metastasis. Although host cells die at low extracellular pH, cancer cells resist, as they are well equipped with transporters and enzymes to regulate intracellular pH homeostasis. A low extracellular pH further activates proteolytic enzymes that remodel the extracellular matrix to facilitate cell migration and invasion. Monocarboxylate transporter MCT1 is a passive transporter of lactic acid that has attracted interest as a target for small-molecule drugs to prevent metastasis. In this study, we present evidence of a function for MCT1 in metastasis beyond its role as a transporter of lactic acid. MCT1 activates transcription factor NF-κB to promote cancer cell migration independently of MCT1 transporter activity. Although pharmacologic MCT1 inhibition did not modulate MCT1-dependent cancer cell migration, silencing or genetic deletion of <i>MCT1 in vivo</i> inhibited migration, invasion, and spontaneous metastasis. Our findings raise the possibility that pharmacologic inhibitors of MCT1-mediated lactic acid transport may not effectively prevent metastatic dissemination of cancer cells. <i>Cancer Res; 77(20); 5591–601. ©2017 AACR</i>.</p></div>

Data from Monocarboxylate Transporter 4 Regulates Maturation and Trafficking of CD147 to the Plasma Membrane in the Metastatic Breast Cancer Cell Line MDA-MB-231

Abstract: <div>Abstract<p>Metastatic cancer cells increase glucose consumption and metabolism via glycolysis, producing large quantities of lactate. 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. CD147, an extracellular matrix metalloproteinase (MMP) inducer, is highly expressed in metastatic cancer cells. Because aerobic glycolysis is a hallmark of metastatic cancer, we examined whether increases in CD147 expression were linked to MCT expression in MDA-MB-231, a highly metastatic breast cancer cell line. MCT4 mRNA and protein expression were increased in MDA-MB-231 cells compared with cells derived from normal mammary tissue. MCT4 colocalized with CD147 in the plasma membrane and in membrane blebs shed from the cell surface. Small interfering RNA–mediated silencing of MCT4 impaired the maturation and trafficking of CD147 to the cell surface, resulting in accumulation of CD147 in the endoplasmic reticulum. Silencing MCT4 also resulted in fewer membrane blebs and decreased migration of MDA-MB-231 cells <i>in vitro</i>. Knockdown of CD147 resulted in loss of MCT4 in the plasma membrane and accumulation of the transporter in endolysosomes. These studies establish for the first time that increased expression of CD147 in metastatic cancer cells is coupled to the up-regulation of MCT4. The synergistic activities of the MCT/CD147 complex could facilitate migration of tumor cells by CD147-mediated MMP induction and lactate-stimulated angiogenesis and hyaluronan production. These data provide a molecular link between two hallmarks of metastatic cancer: the glycolytic switch and increased expression of CD147. [Cancer Res 2007;67(9):4182–9]</p></div>