-
Human Cell Jan 2022Lactate, as the product of glycolytic metabolism and the substrate of energy metabolism, is an intermediate link between cancer cell and tumor microenvironment... (Review)
Review
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.
Topics: Endothelial Cells; Energy Metabolism; Glycolysis; Humans; Isoenzymes; L-Lactate Dehydrogenase; Lactates; Molecular Targeted Therapy; Monocarboxylic Acid Transporters; Neoplasms; Pyruvic Acid; Stromal Cells; Symporters; Tumor Microenvironment
PubMed: 34606041
DOI: 10.1007/s13577-021-00622-z -
Genetic Testing and Molecular Biomarkers Mar 2022Lactate dehydrogenase (LDH) is a marker of injury and disease as it is expressed extensively in numerous cell types and tissues. Moreover it is released during tissue...
Lactate dehydrogenase (LDH) is a marker of injury and disease as it is expressed extensively in numerous cell types and tissues. Moreover it is released during tissue breakdown, and is elevated in cancerous tissues. However, the clinical significance and prognostic value of LDH as a tumor marker have been subject to considerable discussion. In this study, clinical serum LDH data from patients with cervical cancer (CC), CC microarray data, and RNA-seq data were integrated to assess the expression of LDH in CC. A total of 204 patients with newly diagnosed CC and 204 age-matched healthy controls were included to evaluate serum LDH levels in CC and non-cancer samples. External microarrays and RNA-seq datasets were collected for the differential expression analysis of LDH in CC and non-cancer tissue samples. Kaplan-Meier survival curves of the prognostic value of LDH for CC were plotted for RNA-seq data. Functional enrichment analysis was performed for the genes co-expressed with LDH. The data from our in-house clinical cases as well as the data extracted from microarrays and RNA-seq databases demonstrated significant overexpression of LDH in CC samples. Elevated LDH expression levels were associated with poor overall survival in CC patients. The genes co-expressed with LDH were significantly correlated with the biological processes and pathways, associated with nuclear division, the condensed chromosome, protein serine/threonine kinase activity, and the cell cycle. In conclusion, LDH upregulation might serve as a therapeutic and prognostic biomarker for CC.
Topics: Biomarkers, Tumor; Female; Humans; Kaplan-Meier Estimate; L-Lactate Dehydrogenase; Prognosis; Uterine Cervical Neoplasms
PubMed: 35349377
DOI: 10.1089/gtmb.2021.0006 -
International Journal of Molecular... Mar 2023Lactate/malate dehydrogenases (Ldh/Maldh) are ubiquitous enzymes involved in the central metabolic pathway of plants and animals. The role of malate dehydrogenases in...
Lactate/malate dehydrogenases (Ldh/Maldh) are ubiquitous enzymes involved in the central metabolic pathway of plants and animals. The role of malate dehydrogenases in the plant system is very well documented. However, the role of its homolog L-lactate dehydrogenases still remains elusive. Though its occurrence is experimentally proven in a few plant species, not much is known about its role in rice. Therefore, a comprehensive genome-wide in silico investigation was carried out to identify all Ldh genes in model plants, rice and , which revealed Ldh to be a multigene family encoding multiple proteins. Publicly available data suggest its role in a wide range of abiotic stresses such as anoxia, salinity, heat, submergence, cold and heavy metal stress, as also confirmed by our qRT-PCR analysis, especially in salinity and heavy metal mediated stresses. A detailed protein modelling and docking analysis using Schrodinger Suite reveals the presence of three putatively functional L-lactate dehydrogenases in rice, namely OsLdh3, OsLdh7 and OsLdh9. The analysis also highlights the important role of Ser-219, Gly-220 and His-251 in the active site geometry of OsLdh3, OsLdh7 and OsLdh9, respectively. In fact, these three genes have also been found to be highly upregulated under salinity, hypoxia and heavy metal mediated stresses in rice.
Topics: Animals; L-Lactate Dehydrogenase; Oryza; Arabidopsis; Malates; Lactate Dehydrogenases; Evolution, Molecular; Metals, Heavy; Stress, Physiological; Gene Expression Regulation, Plant; Plant Proteins; Phylogeny
PubMed: 36982973
DOI: 10.3390/ijms24065900 -
Nature Communications Oct 2023Mammalian lactate dehydrogenase D (LDHD) catalyzes the oxidation of D-lactate to pyruvate. LDHD mutations identified in patients with D-lactic acidosis lead to deficient...
Mammalian lactate dehydrogenase D (LDHD) catalyzes the oxidation of D-lactate to pyruvate. LDHD mutations identified in patients with D-lactic acidosis lead to deficient LDHD activity. Here, we perform a systematic biochemical study of mouse LDHD (mLDHD) and determine the crystal structures of mLDHD in FAD-bound form and in complexes with FAD, Mn and a series of substrates or products. We demonstrate that mLDHD is an Mn-dependent general dehydrogenase which exhibits catalytic activity for D-lactate and other D-2-hydroxyacids containing hydrophobic moieties, but no activity for their L-isomers or D-2-hydroxyacids containing hydrophilic moieties. The substrate-binding site contains a positively charged pocket to bind the common glycolate moiety and a hydrophobic pocket with some elasticity to bind the varied hydrophobic moieties of substrates. The structural and biochemical data together reveal the molecular basis for the substrate specificity and catalytic mechanism of LDHD, and the functional roles of mutations in the pathogenesis of D-lactic acidosis.
Topics: Animals; Mice; Humans; Acidosis, Lactic; Lactate Dehydrogenases; Lactic Acid; Hydroxy Acids; Binding Sites; L-Lactate Dehydrogenase; Mammals
PubMed: 37863926
DOI: 10.1038/s41467-023-42456-3 -
Cancer Letters Nov 2023Lung adenocarcinoma (LUAD) is one of the most prevalent and aggressive types of lung cancer. Metabolic reprogramming plays a critical role in the development and...
Combined inhibition of pyruvate dehydrogenase kinase 1 and lactate dehydrogenase a induces metabolic and signaling reprogramming and enhances lung adenocarcinoma cell killing.
Lung adenocarcinoma (LUAD) is one of the most prevalent and aggressive types of lung cancer. Metabolic reprogramming plays a critical role in the development and progression of LUAD. Pyruvate dehydrogenase kinase 1 (PDK1) and lactate dehydrogenase A (LDHA) are two key enzymes involved in glucose metabolism, whilst their aberrant expressions are often associated with tumorigenesis. Herein, we investigated the anticancer effects of combined inhibition of PDK1 and LDHA in LUAD in vitro and in vivo and its underlying mechanisms of action. The combination of a PDK1 inhibitor, 64, and a LDHA inhibitor, NHI-Glc-2, led to a synergistic growth inhibition in 3 different LUAD cell lines and more than additively suppressed tumor growth in the LUAD xenograft H1975 model. This combination also inhibited cellular migration and colony formation, while it induced a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS) resulting in mitochondrial depolarization and apoptosis in LUAD cells. These effects were related to modulation of multiple cell signaling pathways, including AMPK, RAS/ERK, and AKT/mTOR. Our findings demonstrate that simultaneous inhibition of multiple glycolytic enzymes (PDK1 and LDHA) is a promising novel therapeutic approach for LUAD.
Topics: Humans; Adenocarcinoma of Lung; Cell Death; Cell Line, Tumor; Cell Proliferation; Glycolysis; L-Lactate Dehydrogenase; Lactate Dehydrogenase 5; Lung Neoplasms; Pyruvate Dehydrogenase Acetyl-Transferring Kinase; Signal Transduction
PubMed: 37805163
DOI: 10.1016/j.canlet.2023.216425 -
Proteomics Aug 2021Serum lactate dehydrogenase (LDH) has been established as a prognostic indicator given its differential expression in COVID-19 patients. However, the molecular...
Serum lactate dehydrogenase (LDH) has been established as a prognostic indicator given its differential expression in COVID-19 patients. However, the molecular mechanisms underneath remain poorly understood. In this study, 144 COVID-19 patients were enrolled to monitor the clinical and laboratory parameters over 3 weeks. Serum LDH was shown elevated in the COVID-19 patients on admission and declined throughout disease course, and its ability to classify patient severity outperformed other biochemical indicators. A threshold of 247 U/L serum LDH on admission was determined for severity prognosis. Next, we classified a subset of 14 patients into high- and low-risk groups based on serum LDH expression and compared their quantitative serum proteomic and metabolomic differences. The results showed that COVID-19 patients with high serum LDH exhibited differentially expressed blood coagulation and immune responses including acute inflammatory responses, platelet degranulation, complement cascade, as well as multiple different metabolic responses including lipid metabolism, protein ubiquitination and pyruvate fermentation. Specifically, activation of hypoxia responses was highlighted in patients with high LDH expressions. Taken together, our data showed that serum LDH levels are associated with COVID-19 severity, and that elevated serum LDH might be consequences of hypoxia and tissue injuries induced by inflammation.
Topics: Adult; Aged; COVID-19; Female; Humans; L-Lactate Dehydrogenase; Male; Middle Aged; Prognosis; Proteomics; Severity of Illness Index
PubMed: 33987944
DOI: 10.1002/pmic.202100002 -
Scientific Reports May 2023L-Lactate is a major waste compound in cultured animal cells. To develop a sustainable animal cell culture system, we aimed to study the consumption of L-lactate using a...
L-Lactate is a major waste compound in cultured animal cells. To develop a sustainable animal cell culture system, we aimed to study the consumption of L-lactate using a photosynthetic microorganism. As genes involved in L-lactate utilization were not found in most cyanobacteria and microalgae, we introduced the NAD-independent L-lactate dehydrogenase gene from Escherichia coli (lldD) into Synechococcus sp. PCC 7002. The lldD-expressing strain consumed L-lactate added to basal medium. This consumption was accelerated by expression of a lactate permease gene from E. coli (lldP) and an increase in culture temperature. Intracellular levels of acetyl-CoA, citrate, 2-oxoglutarate, succinate, and malate, and extracellular levels of 2-oxoglutarate, succinate, and malate, increased during L-lactate utilization, suggesting that the metabolic flux from L-lactate was distributed toward the tricarboxylic acid cycle. This study provides a perspective on L-lactate treatment by photosynthetic microorganisms, which would increase the feasibility of animal cell culture industries.
Topics: Animals; L-Lactate Dehydrogenase; Malates; Escherichia coli; Ketoglutaric Acids; Lactic Acid; Synechococcus; Succinates
PubMed: 37142758
DOI: 10.1038/s41598-023-34289-3 -
Brain and Behavior Jan 2024Ischemic stroke (IS) is one of the major global health problems. It is not clear whether there is a causal relationship between lactate dehydrogenase (LDH) and the risk... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND OBJECTIVE
Ischemic stroke (IS) is one of the major global health problems. It is not clear whether there is a causal relationship between lactate dehydrogenase (LDH) and the risk of IS attacks. The purpose of this study was to investigate whether LDH has a causal relationship with the development of IS.
METHODS
The genome-wide association data of LDH and IS were obtained through a Mendelian randomization-based platform. Single nucleotide polymorphisms (SNP) that were significantly associated with LDH were identified and used as instrumental variables, and a two-sample Mendelian randomization study was used to examine the causal relationship between LDH and IS. The statistical methods included Inverse-variance weighted approach, MR-Egger regression, and weighted median estimator.
RESULTS
We selected 15 SNPs of genome-wide significance from Genome-wide association study database with LDH as instrumental variables. A consistent causal association between LDH and IS was observed by different assessment methods. The results of the inverse-variance weighted method suggested an inverse association between LDH and higher genetic predictability of IS risk (OR, 0.997; 95%CI 0.995-0.999). The weighted median estimate showed consistent results with the MR-Egger method (weighted median estimate: OR, 0.995; 95%CI 0.992-0.999; MR-Egger method: OR, 0.996; 95%CI 0.992-0.999). The inverse-variance weighted method indicates a causal association between LDH and IS (β = -0.002563, SE = 0.00128, p = .0453). MR-Egger analysis (β = -0.004498, SE = 0.001877, p = .03) and the weighted median method suggested that LDH and IS also existed causal relationship (β = -0.004861, SE = 0.001801, p = .00695).
CONCLUSIONS
Our Mendelian randomization results suggest that LDH is inversely associated with the risk of developing IS, and are contrary to the results of previous observational studies.
Topics: Humans; Ischemic Stroke; Genome-Wide Association Study; L-Lactate Dehydrogenase; Mendelian Randomization Analysis; Polymorphism, Single Nucleotide
PubMed: 38376049
DOI: 10.1002/brb3.3352 -
Oral Diseases Jan 2022This study aimed to develop a nomogram to predict the neck occult metastasis in early (T1-T2 cN0) oral squamous cell carcinoma (OSCC).
OBJECTIVE
This study aimed to develop a nomogram to predict the neck occult metastasis in early (T1-T2 cN0) oral squamous cell carcinoma (OSCC).
MATERIALS AND METHODS
The nomogram was developed in a training cohort of 336 early OSCC patients and was validated in a validation cohort including 88 patients. Independent predictors were calculated by univariate and multivariate logistic regression analyses.
RESULTS
In univariate logistical regression analysis, gender, perineural invasion (PNI), blood vessel invasion, mean corpuscular hemoglobin, aspartate aminotransferase, prealbumin, globulin (GLO), lactate dehydrogenase (LDH), serum sodium (NA), and serum chloride were significant associated with neck occult metastasis. Multivariate logistical regression analysis identified PNI (p < .001), LDH (p = .003), GLO (p = .019), and NA (p = .020) as independent predictors of neck occult metastasis. Cut-off values for LDH, GLO, and NA obtained from AUC were 142.5, 26.35, and 139.5, respectively. The nomogram based on PNI and categorical GLO, LDH, and NA exhibited a strong discrimination, with a C-indexes of 0.748 (95%CI = 0.688 to 0.810) in the training cohort and 0.751 (95%CI = 0.639 to 0.863) in the validation cohort.
CONCLUSIONS
A nomogram based on PNI, LDH, GLO, and NA for predicting the risk of neck lymph nodes occult metastasis in OSCC could help surgeons with therapy decision-making.
Topics: Carcinoma, Squamous Cell; Globulins; Humans; L-Lactate Dehydrogenase; Mouth Neoplasms; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Staging; Retrospective Studies; Sodium
PubMed: 33289935
DOI: 10.1111/odi.13750 -
Science Advances Mar 2023Isoenzyme divergence is a prevalent mechanism governing tissue-specific and developmental stage-specific metabolism in mammals. The lactate dehydrogenase (LDH) isoenzyme...
Isoenzyme divergence is a prevalent mechanism governing tissue-specific and developmental stage-specific metabolism in mammals. The lactate dehydrogenase (LDH) isoenzyme spectrum reflects the tissue-specific metabolic status. We found that three tetrameric isoenzymes composed of LDHA and LDHB (LDH-3/4/5) comprise the LDH spectrum in T cells. Genetically deleting or altered the isoenzyme spectrum by removing all heterotetramers and leaving T cells with LDH-1 (the homotetramer of LDHB) or LDH-5 (the homotetramer of LDHA), respectively. Accordingly, deleting suppressed glycolysis, cell proliferation, and differentiation. Unexpectedly, deleting enhanced glycolysis but suppressed T cell differentiation, indicating that an optimal zone of glycolytic activity is required to maintain cell fitness. Mechanistically, the LDH isoenzyme spectrum imposed by LDHA and LDHB is necessary to optimize glycolysis to maintain a balanced nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide hydrogen pool. Our results suggest that the LDH isoenzyme spectrum enables "Goldilocks levels" of glycolytic and redox activity to control T cell differentiation.
Topics: Animals; Isoenzymes; NAD; T-Lymphocytes; L-Lactate Dehydrogenase; Lactate Dehydrogenase 5; Glycolysis; Cell Differentiation; Mammals
PubMed: 36961904
DOI: 10.1126/sciadv.add9554