Lactate shuttle: from substance exchange to regulatory mechanism.

Lactate, as the product of glycolytic metabolism and the substrate of energy metabolism, is an intermediate link between cancer cell and tumor microenvironment metabolism. The exchange of lactate between the two cells via mono-carboxylate transporters (MCTs) is known as the lactate shuttle in cancer. Lactate shuttle is the core of cancer cell metabolic reprogramming between two cells such as aerobic cancer cells and hypoxic cancer cells, tumor cells and stromal cells, cancer cells and vascular endothelial cells. Cancer cells absorb lactate by mono-carboxylate transporter 1 (MCT1) and convert lactate to pyruvate via intracellular lactate dehydrogenase B (LDH-B) to maintain their growth and metabolism. Since lactate shuttle may play a critical role in energy metabolism of cancer cells, components related to lactate shuttle may be a crucial target for tumor antimetabolic therapy. In this review, we describe the lactate shuttle in terms of both substance exchange and regulatory mechanisms in cancer. Meanwhile, we summarize the difference of key proteins of lactate shuttle in common types of cancer.

Prophylactic Treatment of Probiotic and Metformin Mitigates Ethanol-Induced Intestinal Barrier Injury: In Vitro, In Vivo, and In Silico Approaches.

Ethanol depletes intestinal integrity and promotes gut dysbiosis. Studies have suggested the individual role of probiotics and metformin Met in protecting intestinal barrier function from injuries induced by ethanol. The objective of the current study is to investigate the potential mechanism by which coadministration of probiotic Visbiome® (V) and Met blocks the ethanol-induced intestinal barrier dysfunction/gut leakiness utilizing Caco-2 monolayers, a rat model with chronic ethanol injury, and in silico docking interaction models. In Caco-2 monolayers, exposure to ethanol significantly disrupted tight junction (TJ) localization, elevated monolayer permeability, and oxidative stress compared with controls. However, cotreatment with probiotic V and Met largely ameliorated the ethanol-induced mucosal barrier dysfunction, TJ disruption, and gut oxidative stress compared with ethanol-exposed monolayers and individual treatment of either agent. Rats fed with ethanol-containing Lieber-DeCarli liquid diet showed decreased expression of TJ proteins, and increased intestinal barrier injury resulting in pro-inflammatory response and oxidative stress in the colon. We found that co-administration of probiotic V and Met improved the expression of intestinal TJ proteins (ZO-1 and occludin) and upregulated the anti-inflammatory response, leading to reduced ER stress. Moreover, co-administration of probiotic V and Met inhibited the CYP2E1 and NOX gene expression, and increase the translocation of Nrf-2 as well as anti-oxidative genes (SOD, catalase, Gpx, and HO-1), leading to reduced colonic ROS content and malondialdehyde levels. The combined treatment of probiotic V and Met also improved their binding affinities towards HO-1, Nrf-2, SLC5A8, and GPR109A, which could be attributed to their synergistic effect. Our findings based on in-vitro, in-vivo, and in-silico analyses suggest that the combination of probiotic V and Met potentially acts in synergism, attributable to their property of inhibition of inflammation and oxidative stress against ethanol-induced intestinal barrier injury.

Transport function, regulation, and biology of human monocarboxylate transporter 1 (hMCT1) and 4 (hMCT4).

Human monocarboxylate transporter 1 (hMCT1) and 4 (hMCT4) are involved in the proton-dependent transport of monocarboxylates such as L-lactate, which play an essential role in cellular metabolism and pH regulation. hMCT1 and 4 are overexpressed in a number of cancers, and polymorphisms in hMCT1 have been reported to be associated with the prognosis of some cancers. Accordingly, recent advances have focused on the inhibition of these transporters as a novel therapeutic strategy in cancers. To screen for MCT inhibitors for clinical application, it is important to study MCT function and regulation, and the effect of compounds on them, using human-derived cells. In this review, we focus on the transport function, regulation, and biology of hMCT1 and hMCT4, and the effects of genetic variation in these transporters in humans.

In vitro angiogenesis inhibition with selective compounds targeting the key glycolytic enzyme PFKFB3.

Abnormal glycolytic metabolism contributes to angiogenic sprouting involved in atherogenesis. We investigated the potential anti-angiogenic properties of specific 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) inhibitors in endothelial cells (ECs). ECs were treated with PFKFB3 inhibitors (named PA-1 and PA-2) and their effects on metabolic and functional characteristics of ECs were investigated. The anti-glycolytic compound 3-(pyridinyl)- 1-(4-pyridinyl)- 2-propen-1-one (3PO) was used as reference compound. PFKFB3 expression and activity (IC50 about 3-21 nM) was inhibited upon treatment with both compounds. Glucose uptake and lactate export were measured using commercial assays and showed a partial reduction up to 40%. PFKFB3 inhibition increased intracellular lactate accumulation, and reduced expression of monocarboxylate transporters-1 (MCT1) and MCT4. Furthermore, endothelial cell migration and proliferation assays demonstrated significant reduction upon treatment with both compounds. Matrix- metalloproteinase (MMP) activity, measured by gelatin zymography, and expression was significantly reduced (up to 25%). In addition, PA compounds downregulated the expression of VCAM-1, VE-cadherin, VEGFa, VEGFR2, TGF-ß, and IL-1ß, in inflamed ECs. Finally, PA-1 and PA-2 treatment impaired the formation of angiogenic sprouts measured by both morphogenesis and spheroid-based angiogenesis assays. Our data demonstrate that the anti-glycolytic PA compounds may affect several steps involved in angiogenesis. Targeting the key glycolytic enzyme PFKFB3 might represent an attractive therapeutic strategy to improve the efficacy of cancer treatments, or to be applied in other pathologies where angiogenesis is a detrimental factor.

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.

SLC16A1-AS1 enhances radiosensitivity and represses cell proliferation and invasion by regulating the miR-301b-3p/CHD5 axis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), a common type of human malignancies, leads to increasing incidence and fairly high mortality. An increasing number of studies have verified that long noncoding RNAs (lncRNAs) played key roles in the development of multiple human cancers. As a biomarker, SLC16A1-AS1 has been reported in non-small cell lung cancer (NSCLC) and oral squamous cell carcinoma (OSCC). Thus, we decided to investigate whether SLC16A1-AS1 exerts its biological function in HCC. In this study, we discovered that SLC16A1-AS1 was obviously downregulated in HCC tissues and cells. Overexpression of SLC16A1-AS1 inhibited HCC cell proliferation, invasion, and epithelial-mesenchymal transition (EMT) process as well as promoted cell apoptosis. Moreover, SLC16A1-AS1 was confirmed to enhance the radiosensitivity of HCC cells. Molecular mechanism exploration suggested that SLC16A1-AS1 served as a sponge for miR-301b-3p and CHD5 was the downstream target gene of miR-301b-3p in HCC cells. Rescue assays implied that CHD5 knockdown could recover the effects of SLC16A1-AS1 overexpression on HCC cellular processes. In brief, our study clarified that SLC16A1-AS1 acted as a tumor suppressor in HCC by targeting the miR-301b-3p/CHD5 axis, which may be a promising diagnostic biomarker and provide promising treatment for HCC patients.

CRISRP/Cas9-mediated knockout of Mct8 reveals a functional involvement of Mct8 in testis and sperm development in a rat.

Thyroid hormone (TH) has long been believed to play a minor role in male reproduction. However, evidences from experimental model of thyrotoxicosis or hypothyroidism suggests its role in spermatogenesis. Cellular action of TH requires membrane transport via specific transporters such as monocarboxylate transporter 8 (MCT8). SLC16A2 (encodes for MCT8) inactivating mutation in humans can lead to Allan-Herndon Dudley-syndrome, a X-linked psychomotor and growth retardation. These patients present cryptorchidism which suggests a role of MCT8 during spermatogenesis. In this study, we found that Mct8 is highly expressed during early postnatal development and decreases its expression in the adulthood of testis of wild-type male rats. Histological analysis revealed that spermatogonia largely lacks MCT8 expression while spermatocytes and maturing spermatids highly express MCT8. To further understand the role of Mct8 during spermatogenesis, we generated Slc16a2 (encodes MCT8) knockout rats using CRISPR/Cas9. Serum THs (T3 and T4) level were significantly altered in Slc16a2 knockout rats when compared to wild-type littermates during early to late postnatal development. Unlike Slc16a2 knockout mice, Slc16a2 knockout rats showed growth delay during early to late postnatal development. In adult Slc16a2 knockout rats, we observed reduced sperm motility and viability. Collectively, our data unveil a functional involvement of MCT8 in spermatogenesis, underscoring the importance of TH signaling and action during spermatogenesis.

Oil Body Formation in Marchantia polymorpha Is Controlled by MpC1HDZ and Serves as a Defense against Arthropod Herbivores.

The origin of a terrestrial flora in the Ordovician required adaptation to novel biotic and abiotic stressors. Oil bodies, a synapomorphy of liverworts, accumulate secondary metabolites, but their function and development are poorly understood. Oil bodies of Marchantia polymorpha develop within specialized cells as one single large organelle. Here, we show that a class I homeodomain leucine-zipper (C1HDZ) transcription factor controls the differentiation of oil body cells in two different ecotypes of the liverwort M. polymorpha, a model genetic system for early divergent land plants. In flowering plants, these transcription factors primarily modulate responses to abiotic stress, including drought. However, loss-of-function alleles of the single ortholog gene, MpC1HDZ, in M. polymorpha did not exhibit phenotypes associated with abiotic stress. Rather, Mpc1hdz mutant plants were more susceptible to herbivory, and total plant extracts of the mutant exhibited reduced antibacterial activity. Transcriptomic analysis of the mutant revealed a reduction in expression of genes related to secondary metabolism that was accompanied by a specific depletion of oil body terpenoid compounds. Through time-lapse imaging, we observed that MpC1HDZ expression maxima precede oil body formation, indicating that MpC1HDZ mediates differentiation of oil body cells. Our results indicate that M. polymorpha oil bodies, and MpC1HDZ, are critical for defense against herbivory, but not for abiotic stress tolerance. Thus, C1HDZ genes were co-opted to regulate separate responses to biotic and abiotic stressors in two distinct land plant lineages.

Lactic Acid: A Novel Signaling Molecule in Early Pregnancy?

Aerobic glycolysis is a recognized feature shared by tumors, leading to the accumulation of lactic acid in their local microenvironments. Like the tumors, the blastocysts, placenta, trophoblasts and decidual immune cells can also produce a large amount of lactic acid through aerobic glycolysis during the early pregnancy. Moreover, the placenta expresses the transporters of the lactic acid. While several studies have described the role of lactic acid in the tumor microenvironment, especially lactic acid's modulation of immune cells, the role of lactic acid produced during pregnancy is still unclear. In this paper, we reviewed the scientific evidence detailing the effects of lactic acid in the tumor microenvironment. Based on the influence of the lactic acid on immune cells and tumors, we proposed that lactic acid released in the unique uterine environment could have similar effects on the trophoblast cells and immune cells during the early pregnancy.

Thyroid Hormone Transporters.

Thyroid hormone transporters at the plasma membrane govern intracellular bioavailability of thyroid hormone. Monocarboxylate transporter (MCT) 8 and MCT10, organic anion transporting polypeptide (OATP) 1C1, and SLC17A4 are currently known as transporters displaying the highest specificity toward thyroid hormones. Structure-function studies using homology modeling and mutational screens have led to better understanding of the molecular basis of thyroid hormone transport. Mutations in MCT8 and in OATP1C1 have been associated with clinical disorders. Different animal models have provided insight into the functional role of thyroid hormone transporters, in particular MCT8. Different treatment strategies for MCT8 deficiency have been explored, of which thyroid hormone analogue therapy is currently applied in patients. Future studies may reveal the identity of as-yet-undiscovered thyroid hormone transporters. Complementary studies employing animal and human models will provide further insight into the role of transporters in health and disease. (Endocrine Reviews 41: 1 - 55, 2020).

Extracellular lysine 38 plays a crucial role in pH-dependent transport via human monocarboxylate transporter 1.

Human monocarboxylate transporters (hMCTs) are expressed in many tissues and mediate the transport of various substrates across the plasma membrane. Among hMCTs, hMCT1-4 cotransport H+ with monocarboxylates such as pyruvate and l-lactate, implying that these proteins recognize both substrate and H+. However, the mechanism of translocation, and particularly that of hMCT1 pH-dependent transport, remains largely unknown. This study aimed at identifying residues involved in the pH dependence of hMCT1 using a combination of amino acid-modifying reagents, site-directed mutagenesis in a Xenopus laevis oocyte expression system, and homology modeling. We showed that diethyl pyrocarbonate (DEPC), phenylglyoxal (PGO), and 4,4'-diisothiocyanato-2,2'-stilbenedisulfonic acid disodium salt (DIDS), which react with histidine, arginine, and lysine residues respectively, all inhibited hMCT1 activity. Since DEPC, PGO, and DIDS are membrane impermeable reagents, we mutated to other residues individual histidine, arginine, and lysine residues located within the extracellular regions of hMCT1. Analyses of these mutants demonstrated that except for K38, the extracellular basic residues of hMCT1 were not involved in its transport activity and pH dependence. Moreover, analyses of various mutants in which K38 was substituted for another residue and of an hMCT1 homology model focusing on the location of K38 in the three-dimensional structure delineated the mechanism of hMCT1 pH dependence. Collectively, our data indicate that K38 plays an essential role in hMCT1 transport activity. We would like to propose a mechanism whereby K38 is positioned within a hydrophobic and narrow cavity that is part of the transport pathway, and regulates pH-dependent gating of hMCT1.

3-Bromopyruvate inhibits the malignant phenotype of malignantly transformed macrophages and dendritic cells induced by glioma stem cells in the glioma microenvironment via miR-449a/MCT1.

Bromopyruvate (3-BrPA) is a glycolysis inhibitor that has been reported to have a strong anti-tumour effect in many human tumours. Several studies have reported that 3-BrPA could inhibit glioma progression; however, its role on the interstitial cells in the glioma microenvironment has not been investigated. In previous studies, we found that in the glioma microenvironment, glioma stem cells can induce the malignant transformation of macrophages and dendritic cells. In this study, we focused on the effects of 3-BrPA on malignantly transformed macrophages and dendritic cells. First, we found that 3-BrPA inhibited the proliferation of malignantly transformed macrophages and dendritic cells in a dose-dependent and time-dependent manner. Further study indicated that 3-BrPA significantly decreased extracellular lactate and inhibited the clone formation, migration and invasion of malignantly transformed macrophages and dendritic cells. Using an online database and a series of experiments, we demonstrated that 3-BrPA inhibits the malignant progression of malignantly transformed macrophages and dendritic cells via the miR-449a/MCT1 axis. These findings built experimental basis for new approach against glioma.

Lactate Buildup at the Site of Chronic Inflammation Promotes Disease by Inducing CD4+ T Cell Metabolic Rewiring.

Accumulation of lactate in the tissue microenvironment is a feature of both inflammatory disease and cancer. Here, we assess the response of immune cells to lactate in the context of chronic inflammation. We report that lactate accumulation in the inflamed tissue contributes to the upregulation of the lactate transporter SLC5A12 by human CD4+ T cells. SLC5A12-mediated lactate uptake into CD4+ T cells induces a reshaping of their effector phenotype, resulting in increased IL17 production via nuclear PKM2/STAT3 and enhanced fatty acid synthesis. It also leads to CD4+ T cell retention in the inflamed tissue as a consequence of reduced glycolysis and enhanced fatty acid synthesis. Furthermore, antibody-mediated blockade of SLC5A12 ameliorates the disease severity in a murine model of arthritis. Finally, we propose that lactate/SLC5A12-induced metabolic reprogramming is a distinctive feature of lymphoid synovitis in rheumatoid arthritis patients and a potential therapeutic target in chronic inflammatory disorders.

Monocarboxylate Transporter 1 in Brain Diseases and Cancers.

BACKGROUND: Monocarboxylate Transporter 1 (MCT1), an important membrane transport protein, mediates the translocation of monocarboxylates together with protons across biological membranes. Due to its pathological significance, MCT1 plays an important role in the progression of some diseases, such as brain diseases and cancers. METHODS: We summarize the general description of MCT1 and provide a comprehensive understanding of the role of MCT1 in brain diseases and cancers. Furthermore, this review discusses the opportunities and challenges of MCT1- targeting drug-delivery systems in the treatment of brain diseases and cancers. RESULTS: In the brain, loss of MCT1 function is associated with pathologies of degeneration and injury of the nervous system. In tumors, MCT1 regulates the activity of signaling pathways and controls the exchange of monocarboxylates in aerobic glycolysis to affect tumor metabolism, proliferation and invasion. Meanwhile, MCT1 also acts as a good biomarker for the prediction and diagnosis of cancer progressions. CONCLUSION: MCT1 is an attractive transporter in brain diseases and cancers. Moreover, the development of MCT1- based small molecule drugs and MCT1 inhibitors in the clinic is promising. This review systematically summarizes the basic characteristics of MCT1 and its role in brain diseases and cancers, laying the foundation for further research on MCT1.

Knockout of MCT1 results in total absence of spermatozoa, sex hormones dysregulation, and morphological alterations in the testicular tissue.

Lactate is a key metabolite for the normal occurrence of spermatogenesis. In the testis, lactate is produced by the Sertoli cells and transported to germline cells. Monocarboxylate transporters (MCTs) are key players in that process. Among the family of MCTs, MCT1 is at least partly responsible for lactate uptake by the germ cells. We aimed to perform a first assessment of the role of MCT1 in male reproductive potential. Mct1 conditional knockout (cKO) mice were used for morphometric evaluation, testicular morphology, and sperm parameter assessment. Serum steroid hormones levels were also measured. cKO animals showed a decrease in gonadosomatic index, testis weight, and seminiferous tubular diameters. Deletion of MCT1 also causes morphological changes in the organization of the seminiferous tubules and on Sertoli cell morphology. These changes resulted in failure of spermatogenesis with depletion of germ cells and total absence of spermatozoa. MCT1 cKO animals presented also hormonal dysregulation, with a decrease in serum 17ß-estradiol levels. In conclusion, MCT1 is pivotal for male reproductive potential. Absence of MCT1 results in maintenance of undifferentiated spermatogonia pool and compromised sperm production.

Research Trends and Hotspots Analysis Related to Monocarboxylate Transporter 1: A Study Based on Bibliometric Analysis.

Background: Monocarboxylate transport protein 1 (MCT1) has been defined as a critical regulator in tumor energy metabolism, but bibliometric analysis of MCT1 research is rare. This study aimed to comprehensively analyze the global scientific output of MCT1 research and explore the hotspots and frontiers from the past decade. Methods: Publications and their literature information from 2008 to 2018 were retrieved from the Web of Science Core Collection database. We used Microsoft Excel 2016 to detect the trend of annual numbers of publications, and used Citespace V software as the bibliometric method to analyze the research areas, countries, institutions, authors, journals, research hotspots, and research frontiers. Results: A total of 851 publications were identified with an increasing trend. Relevant literature mainly focused on the field of oncology. The most prolific country and institution were the USA and University of Minho, respectively. Baltazar was the most productive author while Halestrap had the highest co-citations. The hottest topics in MCT1 were hypoxia, gene expression, and CD147 over the last decade. The three research frontier topics were proliferation, tumor cell, and resistance. The special role of MCT1 in human tumor cells has become the focus for scholars recently. Conclusion: The development prospects of MCT1 research could be expected and researchers should pay attention to the clinical significance of MCT1 inhibitors as anti-cancer or immunosuppressive drugs and the possibility of drug-resistance formation.

Catalytically inactive carbonic anhydrase-related proteins enhance transport of lactate by MCT1.

Carbonic anhydrases (CA) catalyze the reversible hydration of CO2 to protons and bicarbonate and thereby play a fundamental role in the epithelial acid/base transport mechanisms serving fluid secretion and absorption for whole-body acid/base regulation. The three carbonic anhydrase-related proteins (CARPs) VIII, X, and XI, however, are catalytically inactive. Previous work has shown that some CA isoforms noncatalytically enhance lactate transport through various monocarboxylate transporters (MCT). Therefore, we examined whether the catalytically inactive CARPs play a role in lactate transport. Here, we report that CARP VIII, X, and XI enhance transport activity of the MCT MCT1 when coexpressed in Xenopus oocytes, as evidenced by the rate of rise in intracellular H+ concentration detected using ion-sensitive microelectrodes. Based on previous studies, we suggest that CARPs may function as a 'proton antenna' for MCT1, to drive proton-coupled lactate transport across the cell membrane.

Exposure to Pb and Cd alters MCT4/CD147 expression and MCT4/CD147-dependent lactate transport in mice Sertoli cells cultured in vitro.

Sertoli cells (SCs) provide lactate as an energy substrate to develop germ cells during spermatogenesis. Lead (Pb) and cadmium (Cd) can induce SC toxicity. However, the mechanisms remain unclear. This study aimed to investigate the molecular mechanisms by which Pb and Cd alter lactate transport and production by SCs. Mouse SC line (15P-1 cells) were cultured in the absence and presence of lead acetate (PbAc, 1, 10, 20 and 30 µM) or cadmium chloride (CdCl2, 0.5, 5, 10 and 15 µM) for 24 h. The results showed that PbAc exposure significantly decreased lactate dehydrogenase (LDH) activity and mRNA level, intracellular and extracellular lactate, and MCT4 and CD147 protein levels but increased MCT4 and CD147 mRNA levels. However, PbAc did not alter the glucose uptake, glucose transporters 1 (GLUT1) and 3 (GLUT3) mRNA expression of SCs. Thus, PbAc mainly decreased lactate production by inhibiting LDH activity. In CdCl2-treated SCs, intracellular lactate content increased but extracellular lactate content decreased significantly, P < .05. The glucose uptake, LDH activity, and mRNA expression of GLUT1, GLUT3 and LDH, all significantly increased. But the mRNA and protein levels of MCT4 and CD147 significantly decreased. Moreover, the fluorescence intensity of co-localizations of the MCT4-CD147 complex dose-dependently decreased in the cell membrane. Thus, CdCl2 may reduce lactate export by suppressing MCT4 and CD147 expression. These results suggest that PbAc and CdCl2 disrupt lactate production and transport in mouse SCs by disturbing glycolysis or inhibiting MCT4-CD147 transporter expression and co-localizations.

Interruption of lactate uptake by inhibiting mitochondrial pyruvate transport unravels direct antitumor and radiosensitizing effects.

Lactate exchange between glycolytic and oxidative cancer cells is proposed to optimize tumor growth. Blocking lactate uptake through monocarboxylate transporter 1 (MCT1) represents an attractive therapeutic strategy but may stimulate glucose consumption by oxidative cancer cells. We report here that inhibition of mitochondrial pyruvate carrier (MPC) activity fulfils the tasks of blocking lactate use while preventing glucose oxidative metabolism. Using in vitro 13C-glucose and in vivo hyperpolarized 13C-pyruvate, we identify 7ACC2 as a potent inhibitor of mitochondrial pyruvate transport which consecutively blocks extracellular lactate uptake by promoting intracellular pyruvate accumulation. Also, while in spheroids MCT1 inhibition leads to cytostatic effects, MPC activity inhibition induces cytotoxic effects together with glycolysis stimulation and uncompensated inhibition of mitochondrial respiration. Hypoxia reduction obtained with 7ACC2 is further shown to sensitize tumor xenografts to radiotherapy. This study positions MPC as a control point for lactate metabolism and expands on the anticancer potential of MPC inhibition.

[MCT4 reduces glucose metabolism and promotes apoptosis of prostate cancer cells].

OBJECTIVE: To investigate the effect of monocarboxylate transporter 4 (MCT4) on the apoptosis and glucose metabolism of prostate cancer cells. METHODS: We constructed an adenoviral vector containing shRNA-MCT4 and transfected it into the adenocarcinoma cell lines DU145 and PC-3, using the untransfected vector as the blank control and the negative vector as the negative control (shRNA-NC). We determined the MCT4 expression, lactic acid secretion, glucose consumption and apoptosis rate in different groups of cells. RESULTS: After transfection, the expression of MCT4 in the DU145 and PC-3 cells was significantly lower in the shRNA-MCT4 than in the blank control (P = 0.008 and 0.008) and shRNA-NC groups (P = 0.007 and 0.009), and so were the secretion of lactic acid (P = 0.009 and 0.009; P = 0.009 and 0.008) and single-cell glucose consumption (P = 0.007 and 0.007; P = 0.009 and 0.007). The apoptosis rate of the DU145 cells was remarkably higher in the shRNA-MCT4 than in the blank control and shRNA-NC groups (ï¼»22.11 ± 2.68ï¼½% vs ï¼»9.81 ± 1.24ï¼½% and ï¼»10.01 ± 1.46ï¼½%, P = 0.003 and 0.003), and so was that of the PC-3 cells (ï¼»23.38 ± 3.08ï¼½% vs ï¼»10.21 ± 1.58ï¼½% and ï¼»10.91 ± 1.63ï¼½%, P = 0.004 and 0.004). CONCLUSIONS: Inhibiting the expression of MCT4 can interfere with the glucose metabolism and promote the apoptosis of prostate cancer cells. The MCT4 gene is a potential therapeutic target for the treatment of prostate cancer.