Expression Of Monocarboxylate Transporter Research Articles

Gut cytokines modulate olfaction through metabolic reprogramming of glia.

Infection-induced aversion against enteropathogens is a conserved sickness behaviour that can promote host survival1,2. The aetiology of this behaviour remains poorly understood, but studies in Drosophila have linked olfactory and gustatory perception to avoidance behaviours against toxic microorganisms3-5. Whether and how enteric infections directly influence sensory perception to induce or modulate such behaviours remains unknown. Here we show that enteropathogen infection in Drosophila can modulate olfaction through metabolic reprogramming of ensheathing glia of the antennal lobe. Infection-induced unpaired cytokine expression in the intestine activates JAK-STAT signalling in ensheathing glia, inducing the expression of glial monocarboxylate transporters and the apolipoprotein glial lazarillo (GLaz), and affecting metabolic coupling of glia and neurons at the antennal lobe. This modulates olfactory discrimination, promotes the avoidance of bacteria-laced food and increases fly survival. Although transient in young flies, gut-induced metabolic reprogramming of ensheathing glia becomes constitutive in old flies owing to age-related intestinal inflammation, which contributes to an age-related decline in olfactory discrimination. Our findings identify adaptive glial metabolic reprogramming by gut-derived cytokines as a mechanism that causes lasting changes in a sensory system in ageing flies.

Effects of iodine excess on serum thyrotropin-releasing hormone levels and type 2 deiodinase in the hypothalamus of Wistar rats.

Iodine is an important element in thyroid hormone biosynthesis. Thyroid function is regulated by the hypothalamic-pituitary-thyroid axis. Excessive iodine leads to elevated thyroid-stimulating hormone (TSH) levels, but the mechanism is not yet clear. Type 2 deiodinase (Dio2) is a Se-containing protease that plays a vital role in thyroid function. The purpose of this study was to explore the role of hypothalamus Dio2 in regulating TSH increase caused by excessive iodine and to determine the effects of iodine excess on thyrotropin-releasing hormone (TRH) levels. Male Wistar rats were randomised into five groups and administered different iodine dosages (folds of physiological dose): normal iodine, 3-fold iodine, 6-fold iodine, 10-fold iodine and 50-fold iodine. Rats were euthanised at 4, 8, 12 or 24 weeks after iodine administration. Serum TRH, TSH, total thyroxine (TT4) and total triiodothyronine (TT3) were determined. Hypothalamus tissues were frozen and sectioned to evaluate the expression of Dio2, Dio2 activity and monocarboxylate transporter 8 (MCT8). Prolonged high iodine intake significantly increased TSH expression (P < 0·05) but did not affect TT3 and TT4 levels. Prolonged high iodine intake decreased serum TRH levels in the hypothalamus (P < 0·05). Dio2 expression and activity in the hypothalamus exhibited an increasing trend compared at each time point with increasing iodine intake (P < 0·05). Hypothalamic MCT8 expression was increased in rats with prolonged high iodine intake (P < 0·05). These results indicate that iodine excess affects the levels of Dio2, TRH and MCT8 in the hypothalamus.

Effect of hyperglycemia on fertility in streptozotocin-induced diabetic male Wistar rats: focus on glucose transporters and oxidative stress

BACKGROUND Glucose transporters (GLUTs) and oxidant metabolism are associated with the mechanism of infertility. This study evaluated the impact of hyperglycemia on glucose and oxidant metabolisms of Sertoli cells (SCs).&#x0D; METHODS This study was an animal study to investigate the expression of messenger RNA monocarboxylate transporter 4 (MCT4), GLUT1, GLUT3, nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase, catalase (CAT), and lactate dehydrogenase A (LDHA) of Wistar rats testes that were induced hyperglycemia. Reverse transcription polymerase chain reaction analysis was used. Hyperglycemic state in the Wistar rats was induced by streptozotocin. 24 rats were divided into 3 groups: non-hyperglycemia (control), 2-week, and 4-week hyperglycemic state. All data were collected and analyzed using SPSS version 15.0 (IBM Corp., USA).&#x0D; RESULTS The expression of glucose transporter (GLUT1 and GLUT3), lactate transporter (MCT4), and cellular defense protein against oxidant (Nrf2 and CAT) was significantly increased in the 2-week and 4-week hyperglycemic state groups with p&lt;0.01, respectively.&#x0D; CONCLUSIONS Hyperglycemic state affects the metabolism of SCs. Alteration of GLUTs and oxidative metabolism may indicate metabolic alterations by a prolonged exposure to hyperglycemia that may be responsible for diabetes-related male infertility.

MiR-29a, b, and c regulate SLC5A8 expression in intestinal epithelial cells.

Short-chain fatty acids (SCFAs) produced by bacterial fermentation of dietary fiber exert myriad of beneficial effects including the amelioration of inflammation. SCFAs exist as anions at luminal pH; their entry into the cells depends on the expression and function of monocarboxylate transporters. In this regard, sodium-coupled monocarboxylate transporter-1 (SMCT-1) is one of the major proteins involved in the absorption of SCFA in the mammalian colon. However, very little is known about the mechanisms of regulation of SMCT-1 expression in health and disease. MicroRNAs (miRs) are known to play a key role in modulating gene expression. In silico analysis showed miR-29a, b, and c with highest context score and its binding region was conserved among mammals. The 3'-untranslated region (UTR) of human SMCT-1 gene was cloned into pmirGLO vector upstream of luciferase reporter and transiently transfected with miR-29a, b, and c mimics into Caco-2 and/or T-84 cells. The presence of UTR of this gene significantly decreased luciferase activity compared with empty vector. Cotransfection with miR-29a, b, or c resulted in further decrease in 3'-UTR activity of SMCT-1 luciferase constructs. Mimic transfection significantly decreased SMCT-1 protein expression without altering mRNA expression. Furthermore, the expression of miR-29a and c were significantly lower in mouse colon compared with small intestine, consistent with higher levels of SMCT-1 protein in the colon. Our studies demonstrated a novel finding in which miR-29a, b, and c downregulate SMCT-1 expression in colonic epithelial cells and may partly explain the differential expression of these transporters along the length of the gastrointestinal (GI) tract.NEW & NOTEWORTHY Our study for the first time reports the posttranscriptional regulation of SMCT-1 by miR-29a, b, and c in colonic epithelial cells. We also demonstrate that the expression of these microRNAs is lower in the mouse proximal and distal colon which partially explains the higher expression level of SMCT-1 in the colon compared with small intestine.

Abstract 2330: MCT inhibition as a therapeutic strategy to target Enzalutamide-resistant prostate cancer

Abstract Sayani Bhattacharjee, Jonathan Doan, Rebecca Wynn, Nagalakshmi Nadiminty Enzalutamide is a second-generation anti-androgen used for the treatment of prostate cancer. However, almost all patients develop resistance to this drug, thereby creating an urgent need of identifying new approaches that can overcome said resistance. Using parental and Enzalutamide-resistant C4-2B and 22RV1 cells, we targeted cellular metabolism to beat therapeutic resistance. Prostate cancers are more heterogeneous in their use of energy sources compared with other solid tumors and the most common metabolic end product is lactate, which is toxic to cancer cells upon accumulation. Hence, cancer cells upregulate the expression of monocarboxylate transporters (MCTs) that play a pivotal role in lactate efflux. Different MCT isoforms are differentially expressed across prostate cancer progression and presumably according to cellular demands at different stages. Gradual progression from benign prostate, to prostatic intraepithelial neoplasia, to in-situ carcinoma showed an increase in the expression of MCT2 and MCT4, with MCT4 being expressed in invasive prostate cancers. Based on our preliminary data that the expression of MCTs is higher in prostate cancer cells resistant to enzalutamide, we hypothesized that MCT inhibition may be an attractive therapeutic strategy against enzalutamide-resistant prostate cancer cells. Using cell survival, cell proliferation and clonogenic-ability assays, we found that the suppression of MCT activity using the MCT1/2 antagonists AR-C155858 or AZD3965 and the MCT 4 antagonist Syrosingopine not only diminishes the proliferation and survival of prostate cancer cells, but also re-sensitizes resistant cells to treatment with enzalutamide. We also found that treatment with AR-C155858 or AZD3965 either singly, or in combination with Enzalutamide suppressed prostate cancer cell xenograft growth in SCID mice bearing subcutaneously injected parental or Enzalutamide-resistant C4-2B cells. These findings imply that the MCTs have an intrinsic role in the acquisition of resistance to therapy. Citation Format: MCT inhibition as a therapeutic strategy to target Enzalutamide-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2330.

MCT4 is induced by metastasis-enhancing pathogenic mitochondrial NADH dehydrogenase gene mutations and can be a therapeutic target

Pathogenic mitochondrial NADH dehydrogenase (ND) gene mutations enhance the invasion and metastasis of various cancer cells, and they are associated with metastasis in human non-small cell lung cancer (NSCLC). Moreover, monocarboxylate transporter 4 (MCT4) is overexpressed in solid cancers and plays a role in cancer cell proliferation and survival. Here, we report that MCT4 is exclusively expressed in mouse transmitochondrial cybrids with metastasis-enhancing pathogenic ND6 mutations. A high level of MCT4 is also detected in human NSCLC cell lines and tissues predicted to carry pathogenic ND mutations and is associated with poor prognosis in NSCLC patients. MCT4 expression in the cell lines is suppressed by N-acetyl-L-cysteine. Phosphatidylinositol-3 kinase (PI3K), AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) are involved in the regulation of MCT4 expression in the transmitochondrial cybrid cells. An MCT1/4 inhibitor effectively kills NSCLC cells with predicted pathogenic ND mutations, but an MCT1/2 inhibitor does not have the same effect. Thus, MCT4 expression is augmented by pathogenic ND mutations and could be a biomarker and a therapeutic target in pathogenic ND mutation-harbouring metastatic tumours.

Loss of basigin expression in uterine cells leads to subfertility in female mice†.

Basigin (BSG) is a transmembrane glycoprotein involved in cell proliferation, angiogenesis, and tissue remodeling. BSG has been shown to be essential for male and female reproduction although little is known about its role in normal uterine function. To study the potential function of BSG in the female reproductive tract, we generated mice with conditional knockout of Bsg in uterine cells using progesterone receptor-Cre and hypothesized that BSG is required for normal pregnancy in mice. Fertility study data showed that the conditional knockout mice had significantly reduced fertility compared to controls. Ovarian function of the conditional knockout mice appeared normal with no difference in the number of superovulated oocytes collected or in serum progesterone levels between the conditional knockout and the control mice. Uterine tissues collected at various times of gestation showed increased abnormalities in implantation, decidualization, placentation, and parturition in the conditional knockout mice. Uterine cross sections on Day 5 of pregnancy showed implantation failure and abnormal uterine epithelial differentiation in a large proportion of the conditional knockout mice. There was a compromised decidual response to artificial decidualization stimuli and decreased mRNA and protein levels for decidualization genes in the uteri of the conditional knockout mice. We also observed altered protein expression of monocarboxylate transporter 1 (MCT1), as well as impaired angiogenesis in the conditional knockout uteri compared to the controls. These results support that BSG is required for successful pregnancy through its functions in implantation and decidualization.

Role of cardiac hypoxia in the pathogenesis of sudden death syndrome in broiler chickens – A metabolic and molecular study

Sudden death syndrome (SDS) is an economically important disorder in broiler chickens with unknown aetiology. The aim of the present study was to evaluate the metabolic and molecular alterations related to hypoxia in the myocardium of broiler chickens with SDS. Samples from the cardiac muscle of internal control broiler chickens (ICs) (n = 36) and chickens having died of SDS (n = 36) were obtained during the rearing period. The activities of lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) and the concentration of lactate were measured in the cardiac tissue using available commercial kits. The expression of hypoxia-inducing factor 1α (HIF1α), glucose transporter 1 (GLUT1), pyruvate dehydrogenase kinase 4 (PDHK4) and monocarboxylate transporter 4 (MCT4) genes was determined in the myocardium by real-time PCR analysis. The results showed the elevation of lactate level and activities of LDH and CPK in the cardiac muscle of SDS-affected chickens compared with the IC birds (P < 0.05). The cardiac muscle expression of HIF1α, MCT4 and GLUT1 genes was increased, while the PDHK4 mRNA level was decreased in the SDS-affected group compared to those in the IC chickens (P < 0.05). Our results showed that metabolic remodelling associated with hypoxia in the cardiac tissues may have an important role in the pathogenesis of cardiac insufficiency and SDS in broiler chickens.

Activation of Hippocampal IR/IRS-1 Signaling Contributes to the Treatment with Zuogui Jiangtang Jieyu Decoction on the Diabetes-Related Depression.

Background Zuogui Jiangtang Jieyu decoction (ZJJ) is mainly used for the treatment of diabetes-related depression in current clinical applications and research. This study aims to investigate whether the brain IR/IRS-1 signaling pathway is involved in the therapeutic effect of ZJJ on depression-like behavior in diabetic rats. Methods Sprague–Dawley rats were fed with high-fat diet and subjected to streptozotocin injection to establish the diabetes animal model. After treatment with different doses of ZJJ (20.530 g/kg or 10.265 g/kg) for 4 weeks, the blood glucose level and peripheral insulin resistance were measured. The forced-swimming test (FST) and Morris water maze test (MWMT) were applied for the mood and cognitive function assessment. Then, the Western blot method was used to analyze the protein levels of insulin receptor (IR), insulin receptor substrate-1 (IRS-1), phosphatidylonositol-3-kinase (PI3K), and protein kinase B (PKB, also as known as AKT) in the hippocampus of diabetic rats. Meanwhile, the immunofluorescence method was performed to analyze the above proteins' expression in the neuron and astrocyte. At last, the levels of glycogen, lactate, and ATP were tested by the ELISA method. Additionally, the insulin-sensitive glucose transporter 4 (GLUT4) and the lactate transporter monocarboxylate transporter 4 (MCT4) were analyzed by the Western blot method. Results ZJJ administration significantly decreased the level of blood glucose and improved the peripheral insulin resistance in diabetic rats. Besides, ZJJ attenuated the depression-like behavior and the cognitive dysfunction in rats with diabetes. Furthermore, we found the upregulation of protein expression of phospho-IR, phospho-IRS-1, phospho-PI3K, and phospho-AKT in the hippocampus of diabetic rats after being treated with ZJJ. Moreover, the above proteins are increased not only in the neuron but also in the astrocyte after ZJJ administration. In addition, ZJJ increased the content of ATP, glycogen, and lactate, as well as the expression of GLUT4 and MCT4 in the hippocampus of diabetic rats. Conclusions These findings suggest that ZJJ improves the depression-like behavior of diabetic rats by activating the IR/IRS-1 signaling pathway in both hippocampal neuron and astrocyte. And the brain IR/IRS-1 signaling pathway plays an important role in astrocyte-neuron metabolic coupling, providing a potential mechanism by which the IR/IRS-1 signaling pathway may contribute to the treatment of ZJJ on diabetes-related depression.

Pinocembrin attenuates hemorrhagic transformation after delayed t-PA treatment in thromboembolic stroke rats by regulating endogenous metabolites.

Hemorrhagic transformation (HT) is a common serious complication of stroke after thrombolysis treatment, which limits the clinical use of tissue plasminogen activator (t-PA). Since early diagnosis and treatment for HT is important to improve the prognosis of stroke patients, it is urgent to discover the potential biomarkers and therapeutic drugs. Recent evidence shows that pinocembrin, a natural flavonoid compound, exerts anti-cerebral ischemia effect and expands the time window of t-PA. In this study, we investigated the effect of pinocembrin on t-PA-induced HT and the potential biomarkers for HT after t-PA thrombolysis, thereby improving the prognosis of stroke. Electrocoagulation-induced thrombotic focal ischemic rats received intravenous infusion of t-PA (10 mg/kg) 6 h after ischemia. Administration of pinocembrin (10 mg/kg, iv) prior t-PA infusion significantly decreased the infarct volume, ameliorated t-PA-induced HT, and protected blood-brain barrier. Metabolomics analysis revealed that 5 differential metabolites in the cerebral cortex and 16 differential metabolites in serum involved in amino acid metabolism and energy metabolism were significantly changed after t-PA thrombolysis, whereas pinocembrin administration exerted significant intervention effects on these metabolites. Linear regression analysis showed that lactic acid was highly correlated to the occurrence of HT. Further experiments confirmed that t-PA treatment significantly increased the content of lactic acid and the activity of lactate dehydrogenase in the cerebral cortex and serum, and the expression of monocarboxylate transporter 1(MCT 1) in the cerebral cortex; pinocembrin reversed these changes, which was consistent with the result of metabolomics. These results demonstrate that pinocembrin attenuates HT after t-PA thrombolysis, which may be associated with the regulation of endogenous metabolites. Lactic acid may be a potential biomarker for HT prediction and treatment.

Liquid Biopsy Targeting Monocarboxylate Transporter 1 on the Surface Membrane of Tumor-Derived Extracellular Vesicles from Synovial Sarcoma.

Simple SummarySynovial sarcoma (SS) is associated with a high risk of recurrence and poor prognosis, and no biomarker useful in monitoring tumor burden exists. We identified monocarboxylate transporter 1 (MCT1) expressed in extracellular vesicles (EVs) derived from synovial sarcoma as a potential such marker. Circulating levels of MCT1+CD9+ EVs were significantly correlated with tumor volume in a SS mouse model. Serum levels of MCT1+CD9+ EVs reflected tumor burden and treatment response in SS patients. Patients with MCT1 expression on the plasma membrane have significantly worse overall survival than those with nuclear expression. Silencing of MCT1 reduced the malignant phenotype including cellular viability, migration, and invasion of SS cells. MCT1 may thus be a promising novel target for liquid biopsies and a novel therapeutic target.The lack of noninvasive biomarkers that can be used for tumor monitoring is a major problem for soft-tissue sarcomas. Here we describe a sensitive analytical technique for tumor monitoring by detecting circulating extracellular vesicles (EVs) of patients with synovial sarcoma (SS). The proteomic analysis of purified EVs from SYO-1, HS-SY-II, and YaFuSS identified 199 common proteins. DAVID GO analysis identified monocarboxylate transporter 1 (MCT1) as a surface marker of SS-derived EVs, which was also highly expressed in SS patient-derived EVs compared with healthy individuals. MCT1+CD9+ EVs were also detected from SS-bearing mice and their expression levels were significantly correlated with tumor volume (p = 0.003). Furthermore, serum levels of MCT1+CD9+ EVs reflected tumor burden in SS patients. Immunohistochemistry revealed that MCT1 was positive in 96.7% of SS specimens and its expression on the cytoplasm/plasma membrane was significantly associated with worse overall survival (p = 0.002). Silencing of MCT1 reduced the cellular viability, and migration and invasion capability of SS cells. This work describes a new liquid biopsy technique to sensitively monitor SS using circulating MCT1+CD9+ EVs and indicates the therapeutic potential of MCT1 in SS.

High expression of monocarboxylate transporter 4 (MCT 4), but not MCT 1, predicts poor prognosis in patients with non-small cell lung cancer.

BackgroundThe monocarboxylate transporter (MCT) family especially MCT1 and MCT4 have been recognized to play an important role in lactate transport, a key glycolytic product. The expression of MCT1 and MCT4 expression was previously found to be related to poor outcome in various cancer types. In this study, we investigated the expression status of MCT1 and MCT4 and their relationship with prognosis in non-small cell lung cancer (NSCLC).MethodsExpression of MCT4 and MCT1 in NSCLC tumor and adjacent lung tissues were detected by immunohistochemistry. Kaplan-Meier plots were used to evaluate two proteins’ prognostic role, and the log-rank test obtained the P value. For multivariate analysis, the Cox proportional-hazards regression method was performed.ResultsHigh MCT4 and MCT1 expression was observed in cancer cells, with a rate of 45% for MCT4 versus 15% for MCT1 among all NSCLC patients. High expression of MCT4, and not MCT1, was associated with worse overall survival (OS) [hazard ratio (HR) =1.96 (1.06–3.75), P=0.032] and progression-free survival (PFS) [HR =1.72 (1.05–2.93), P=0.032] in NSCLC patients. In our multivariate analysis, advanced cancer stage and high MCT4 level were identified as independent predictive indicators for both PFS [HR(MCT4) =1.888 (1.114–3.199), P=0.018 and OS [HR (MCT4) =2.421 (1.271–4.610), P=0.007]. Subgroup and interaction analyses were also performed in different clinical characteristic groups and no significant differences were observed.ConclusionsHigh MCT4 expression is a predictive marker for worse outcome in NSCLC patients.

Prognostic value of glycolysis markers in head and neck squamous cell carcinoma: a meta-analysis.

Glycolysis markers including glucose transporter 1 (GLUT1), monocarboxylate transporter 4 (MCT4), hexokinase 2 (HK2), pyruvate kinase M2 (PKM2) and glucose transporter 4 (GLUT4) play vital roles in head and neck squamous cell carcinoma (HNSCC). However, their prognostic value in HNSCC is still controversial. In this meta-analysis, we searched the PubMed, Web of Science and Cochrane Library databases and included thirty-seven studies (3272 patients) that met the inclusion criteria. Higher expression levels of the glycolysis markers in tumor tissues correlated with poorer overall survival (OS; P < 0.001), disease-free survival (DFS; P = 0.03) and recurrence-free survival (RFS; P < 0.001) of HNSCC patients. Subgroup and sensitivity analyses demonstrated that higher expression levels of GLUT1 (P < 0.001), MCT4 (P = 0.002), HK2 (P = 0.002) and PKM2 (P < 0.001) correlated with poorer OS among HNSCC patients. Higher expression of MCT4 (P < 0.001) and PKM2 (P = 0.008) predicted poorer DFS among HNSCC patients. However, GLUT4 expression levels did not associate with clinical outcomes in HNSCC patients. These results demonstrate that glycolysis markers, such as GLUT1, MCT4, HK2 and PKM2, are potential prognostic predictors and therapeutic targets in HNSCC.

Monocarboxylate transporter-1 (MCT1) protein expression in head and neck cancer affects clinical outcome

Treatment of locally advanced, unresectable head and neck squamous cell carcinoma (HNSCC) often yields only modest results with radiochemotherapy (RCT) as standard of care. Prognostic features related to outcome upon RCT might be highly valuable to improve treatment. Monocarboxylate transporters-1 and -4 (MCT1/MCT4) were evaluated as potential biomarkers. A cohort of HNSCC patients without signs for distant metastases was assessed eliciting 82 individuals eligible whereof 90% were diagnosed with locally advanced stage IV. Tumor specimens were stained for MCT1 and MCT4 in the cell membrane by immunohistochemistry. Obtained data were evaluated with respect to overall (OS) and progression-free survival (PFS). Protein expression of MCT1 and MCT4 in cell membrane was detected in 16% and 85% of the tumors, respectively. Expression of both transporters was not statistically different according to the human papilloma virus (HPV) status. Positive staining for MCT1 (n = 13, negative in n = 69) strongly worsened PFS with a hazard ratio (HR) of 3.1 (95%-confidence interval 1.6–5.7, p < 0.001). OS was likewise affected with a HR of 3.8 (2.0–7.3, p < 0.001). Multivariable Cox regression confirmed these findings. We propose MCT1 as a promising biomarker in HNSCC treated by primary RCT.

The effects of different training modalities on monocarboxylate transporters MCT1 and MCT4, hypoxia inducible factor-1α (HIF-1α), and PGC-1α gene expression in rat skeletal muscles.

The research literature suggests that different training modalities cause various patterns in training-induced genes expression. This study aimed to investigate the effects of moderate intensity continuous training (MICT) and isocaloric high intensity interval training (HIIT) on gene expression of monocarboxylate transporter 1 (MCT1) and 4 (MCT4), Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), and hypoxia inducible factor-1α (HIF-1α) in soleus and extensor digitorum longus (EDL) skeletal muscles of rats. Thirty male Sprague-Dawley rats were divided into 3 groups of control, MICT, and HIIT. Training protocols were performed according to the principle of overload for 8weeks and 5 sessions per week. Then, the soleus and EDL muscles were extracted and the expression levels were analyzed using the real time PCR method. In the MICT group, only the EDL HIF-1α mRNA level was significantly higher than that of the control group (p < 0.05). In the HIIT group, however, mRNA levels of MCT4, PGC-1α, and HIF-1α in both muscles were significantly higher than those of the control group (p < 0.05). The comparison between the two training methods demonstrated that the gene expression levels of soleus and EDL MCT4, soleus PGC-1α, and soleus HIF-1α were significantly higher in the HIIT group compared to the MICT group (p < 0.05). There were also significant positive correlations between all mRNA levels of HIF-1α and corresponding mRNA levels of MCT4 (p < 0.05). HIIT caused greater positive responses in the gene expression of MCT4, PGC-1α, and HIF-1α compared to MICT.

Monocarboxylate transporter 1 promotes proliferation and invasion of renal cancer cells by mediating acetate transport.

One hallmark of renal cell carcinoma (RCC) is metabolic reprogramming, which involves elevation of glycolysis and upregulation of lipid metabolism. However, the mechanism of metabolic reprogramming is incompletely understood. Monocarboxylate transporter 1 (MCT1) promotes transport for lactate and pyruvate, which are crucial for cell metabolism. The aim of present study was to investigate the function of MCT1 on RCC development and its mechanism on metabolic reprogramming. The results showed that MCT1 messenger RNA and protein levels significantly increased in cancer tissues of ccRCC compared to normal tissue. MCT1 was further found to mainly located in the cell membrane of RCC. The knockdown of MCT1 by RNAi significantly inhibited proliferation and migration of 786-O and ACHN cells. MCT1 also induced the expressions of proliferation marker Ki-67 and invasion marker SNAI1. Moreover, we also showed that acetate treatment could upregulate the expression of MCT1, but not other MCT isoforms. On the other hand, MCT1 was involved in acetate transport and intracellular histone acetylation. In summary, this study revealed that MCT1 is abnormally high in ccRCC and promotes cancer development. The regulatory effect of MCT1 on cell proliferation and invasion maybe mediated by acetate transport.

Monocarboxylate transporter 9 (MCT9) is down-regulated in renal cell carcinoma.

The renal cell carcinoma (RCC) incidences are continuously increasing, however, their proper characterization remains difficult. Mammalian kidneys require large amounts of energy, and monocarboxylate transporter (MCT) gene family is responsible for the transport of monocarboxylic compounds across plasma membranes. A total of 14 MCT members have been identified in humans, which show highly distinct substrate affinities and tissue distributions. To understand the yet-uncharacterized renal cancer-specific role of MCTs, we identified MCT members that are differentially regulated during the renal tumor progression. We examined the expression level of MCT members in renal cell tumors and their relationship with survival rate of patients using a public database. Quantitative RT-PCR and northern blotting were performed to validate the expression of MCTs. Anti-MCT9 antiserum was raised in rabbit and used to examine MCT9 expression in normal and tumor tissue arrays. Effect of MCT9 overexpression on cell proliferation was measured using renal cancer cell lines. MCT9 was found to be abundantly and exclusively expressed in human kidney cells, and was highly downregulated in renal cancers. Kaplan-Meier plotter analysis revealed an increased survival rate of MCT9 high-expressing RCC patients. MCT9 proteins were detected in normal kidney tissue sections and their overexpression clearly attenuated renal cell proliferation. MCT9 was identified as a novel highly downregulated gene in renal cell cancer, and its overexpression clearly attenuated RCC cell proliferation. Thus, functional analysis of MCT9 may help in deciphering a yet-undiscovered kidney-specific energy metabolism during renal tumor progression.

Comprehensive Analysis of Monocarboxylate Transporter 4 (MCT4) expression in breast cancer prognosis and immune infiltration via integrated bioinformatics analysis

ABSTRACT Lactate blunts the anticancer immune response in breast cancer (BC). However, little is known about the exact effect of lactate transporters such as monocarboxylate transporter 4 (MCT4) on immunotherapy. In this study, we investigated the expression status and prognostic value of MCT4 in BC through large-scale transcriptome data. Our results showed that MCT4 was overexpressed in BC, particularly in the basal-like molecular subtype. Overexpression of MCT4 was significantly correlated with high BC lesion grade and poor prognosis. Enrichment analysis indicated that the MCT4-related genes were involved in immune- and metabolism-related bioprocesses, such as myeloid leukocyte activation, the adaptive immune system, and catabolic process. We also found that the expression of MCT4 in BC lesions was associated with immune cell infiltration and glycolytic rate-limiting enzymes like pyruvate kinase M2 (PKM2) and hexokinases-3 (HK3). Our observations indicate that MCT4 may play a pivotal role in the maintenance of the tumor immune microenvironment (TIME) through metabolic reprogramming. The enzymes of the glycolysis pathway (MCT4, PKM2, and HK3) may thus serve as new targets to modulate the TIME and enhance immunotherapy efficiency.

MCT1 Deletion in Oligodendrocyte Lineage Cells Causes Late-Onset Hypomyelination and Axonal Degeneration

SUMMARYOligodendrocytes (OLs) are important for myelination and shuttling energy metabolites lactate and pyruvate toward axons through their expression of monocarboxylate transporter 1 (MCT1). Recent studies suggest that loss of OL MCT1 causes axonal degeneration. However, it is unknown how widespread and chronic loss of MCT1 in OLs specifically affects neuronal energy homeostasis with aging. To answer this, MCT1 conditional null mice were generated that allow for OL-specific MCT1 ablation. We observe that MCT1 loss from OL lineage cells is dispensable for normal myelination and axonal energy homeostasis early in life. By contrast, loss of OL lineage MCT1 expression with aging leads to significant axonal degeneration with concomitant hypomyelination. These data support the hypothesis that MCT1 is important for neuronal energy homeostasis in the aging central nervous system (CNS). The reduction in OL MCT1 that occurs with aging may enhance the risk for axonal degeneration and atrophy in neurodegenerative diseases.

Participation of Monocarboxylate Transporter 8, But Not P-Glycoprotein, in Carrier-Mediated Cerebral Elimination of Phenytoin across the Blood-Brain Barrier.

In this study, we investigated in detail the transport of phenytoin across the blood-brain barrier (BBB) to identify the transporter(s) involved in BBB-mediated phenytoin efflux from the brain. We evaluated the brain-to-blood efflux transport of phenytoin in vivo by determining the brain efflux index (BEI) and uptake in brain slices. We additionally conducted brain perfusion experiments and BEI studies in P-glycoprotein (P-gp)-deficient mice. In addition, we determined the mRNA expression of monocarboxylate transporter (MCT) in isolated brain capillaries and performed phenytoin uptake studies in MCT-expressing Xenopus oocytes. [14C]Phenytoin brain efflux was time-dependent with a half-life of 17min in rats and 31min in mice. Intracerebral pre-administration of unlabeled phenytoin attenuated BBB-mediated phenytoin efflux transport, suggesting carrier-mediated phenytoin efflux transport across the BBB. Pre-administration of P-gp substrates in rats and genetic P-gp deficiency in mice did not affect BBB-mediated phenytoin efflux transport. In contrast, pre-administration of MCT8 inhibitors attenuated phenytoin efflux. Moreover, rat MCT8-expressing Xenopus oocytes exhibited [14C]phenytoin uptake, which was inhibited by unlabeled phenytoin. Our data suggest that MCT8 at the BBB participates in phenytoin efflux transport from the brain to the blood.