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Theranostics 2022Chemoresistance to 5-fluorouracil (5-FU) is a major barrier to influence the treatment efficiency of colorectal cancer (CRC) patients, while the precise molecular...
Chemoresistance to 5-fluorouracil (5-FU) is a major barrier to influence the treatment efficiency of colorectal cancer (CRC) patients, while the precise molecular mechanisms underlying 5-FU resistance remain to be fully elucidated. The metabolic profiles including ATP generation, glucose consumption, lactate generation, and oxygen consumption rate (OCR) in 5-FU resistant CRC cells were compared with those in their parental cells. Subsequently, a series of and experiments were carried out to investigate the mechanisms responsible for metabolic reprogramming of 5-FU resistant CRC cells. We found that 5-FU resistant CRC cells showed increased levels of ATP generation, glucose consumption, lactate generation, and OCR as compared with those in their parental cells. Further, increased levels of mRNA N-methyladenosine (mA) and methyltransferase-like 3 (METTL3) were observed in 5-FU resistant CRC cells. Inhibition or knockdown of METTL3 can suppress glycolysis and restore chemosensitivity of 5-FU resistant CRC cells. Mechanistically, METTL3 enhances the expression of LDHA, which catalyzes the conversion of pyruvate to lactate, to trigger glycolysis and 5-FU resistance. METTL3 can increase the transcription of LDHA via stabilizing mRNA of hypoxia-inducible factor (HIF-1α), further, METTL3 also triggers the translation of LDHA mRNA via methylation of its CDS region and recruitment of YTH domain-containing family protein 1 (YTHDF1). Targeted inhibition of METTL3/LDHA axis can significantly increase the and 5-FU sensitivity of CRC cells. Our study indicates that METTL3/LDHA axis-induced glucose metabolism is a potential therapy target to overcome 5-FU resistance in CRC cells.
Topics: Adenosine; Adenosine Triphosphate; Cell Line, Tumor; Colorectal Neoplasms; Drug Resistance, Neoplasm; Fluorouracil; Glucose; HCT116 Cells; Humans; L-Lactate Dehydrogenase; Lactates; Methyltransferases; RNA, Messenger
PubMed: 35832094
DOI: 10.7150/thno.73746 -
Blood May 2022Translation is essential for megakaryocyte (MK) maturation and platelet production. However, how the translational pathways are regulated in this process remains...
Translation is essential for megakaryocyte (MK) maturation and platelet production. However, how the translational pathways are regulated in this process remains unknown. In this study, we found that MK/platelet-specific lactate dehydrogenase A (LdhA) knockout mice exhibited an increased number of platelets with remarkably accelerated MK maturation and proplatelet formation. Interestingly, the role of LDHA in MK maturation and platelet formation did not depend on lactate content, which was the major product of LDHA. Mechanism studies revealed that LDHA interacted with eukaryotic elongation factor 2 (eEF2) in the cytoplasm, controlling the participation of eEF2 in translation at the ribosome. Furthermore, the interaction of LDHA and eEF2 was dependent on nicotinamide adenine dinucleotide (NADH), a coenzyme of LDHA. NADH-competitive inhibitors of LDHA could release eEF2 from the LDHA pool, upregulate translation, and enhance MK maturation in vitro. Among LDHA inhibitors, stiripentol significantly promoted the production of platelets in vivo under a physiological state and in the immune thrombocytopenia model. Moreover, stiripentol could promote platelet production from human cord blood mononuclear cell-derived MKs and also have a superposed effect with romiplostim. In short, this study shows a novel nonclassical function of LDHA in translation that may serve as a potential target for thrombocytopenia therapy.
Topics: Animals; Blood Platelets; Elongation Factor 2 Kinase; Enzyme Inhibitors; L-Lactate Dehydrogenase; Megakaryocytes; Mice; Mice, Knockout; NAD; Peptide Elongation Factor 2; Thrombocytopenia; Thrombopoiesis
PubMed: 35176139
DOI: 10.1182/blood.2022015620 -
Advances in Experimental Medicine and... 2015Lactate dehydrogenase (LDH) among many biochemical parameters represents a very valuable enzyme in patients with cancer with possibility for easy routine measurement in... (Review)
Review
Lactate dehydrogenase (LDH) among many biochemical parameters represents a very valuable enzyme in patients with cancer with possibility for easy routine measurement in many clinical laboratories. Previous studies where mostly based on investigated LDH in serum of patients with cancer with aims to estimate their clinical significance. The new directions in investigation of LDH where based on the principle that tumor cells release intracellular enzymes trough damaged cell membrane, that is mostly consequence in intracellular mitochondrial machinery alteration, and apoptosis deregulation. This consideration can be used not only in-vitro assays, but also in respect to clinical characteristics of tumor patients. Based on new techniques of molecular biology it is shown that intracellular characteristics of LDH enzyme are very sensitive indicators of the cellular metabolic state, aerobic or anaerobic direction of glycolysis, activation status and malignant transformation. Using different molecular analyses it is very useful to analyzed intracellular LDH activity in different cell line and tumor tissues obtained from patients, not only to understanding complexity in cancer biochemistry but also in early clinical diagnosis. Based on understandings of the LDH altered metabolism, new therapy option is created with aims to blocking certain metabolic pathways and stop tumors growth.
Topics: Biomarkers, Tumor; Glucose; Humans; Isoenzymes; L-Lactate Dehydrogenase
PubMed: 26530363
DOI: 10.1007/978-94-017-7215-0_8 -
Nature Metabolism Dec 2022The glycolytic enzyme lactate dehydrogenase A (LDHA) is frequently overexpressed in cancer, which promotes glycolysis and cancer. The oncogenic effect of LDHA has been...
The glycolytic enzyme lactate dehydrogenase A (LDHA) is frequently overexpressed in cancer, which promotes glycolysis and cancer. The oncogenic effect of LDHA has been attributed to its glycolytic enzyme activity. Here we report an unexpected noncanonical oncogenic mechanism of LDHA; LDHA activates small GTPase Rac1 to promote cancer independently of its glycolytic enzyme activity. Mechanistically, LDHA interacts with the active form of Rac1, Rac1-GTP, to inhibit Rac1-GTP interaction with its negative regulator, GTPase-activating proteins, leading to Rac1 activation in cancer cells and mouse tissues. In clinical breast cancer specimens, LDHA overexpression is associated with higher Rac1 activity. Rac1 inhibition suppresses the oncogenic effect of LDHA. Combination inhibition of LDHA enzyme activity and Rac1 activity by small-molecule inhibitors displays a synergistic inhibitory effect on breast cancers with LDHA overexpression. These results reveal a critical oncogenic mechanism of LDHA and suggest a promising therapeutic strategy for breast cancers with LDHA overexpression.
Topics: Animals; Mice; Lactate Dehydrogenase 5; L-Lactate Dehydrogenase; GTP Phosphohydrolases; Isoenzymes; Neoplasms; Guanosine Triphosphate
PubMed: 36536137
DOI: 10.1038/s42255-022-00708-4 -
Clinical and Translational Medicine Jan 2022Protein arginine methylation has emerged a pivotal role in cancer progression. However, the role of protein arginine methyltransferase 3 (PRMT3) in hepatocellular...
BACKGROUND
Protein arginine methylation has emerged a pivotal role in cancer progression. However, the role of protein arginine methyltransferase 3 (PRMT3) in hepatocellular carcinoma (HCC) remains unknown.
METHODS
The expression pattern of PRMT3 in HCC was analysed using quantitative real-time-polymerase chain reaction (qRT-PCR), Western blotting and immunohistochemistry assays. Loss- and gain-of-function experiments were carried out to determine the oncogenic role of PRMT3 in HCC. Glucose consumption and lactate production assays, seahorse bioscience, mass spectrometry, co-immunoprecipitation, metabonomic analysis and site-specific mutation experiments were used to explore the underlying molecular mechanisms. Furthermore, a xenograft mouse model was established to investigate the effects of PRMT3 and its inhibitor, SGC707, treatment on tumour growth in vivo.
RESULTS
The expression of PRMT3 was significantly upregulated in HCC, with high expression of which correlated with poor prognosis. PRMT3 knockdown led to the decrease in proliferation, glycolysis of HCC cells and tumour growth, whilst its overexpression showed opposite results. The catalytic activity of PRMT3 was important in mediating these biological processes. Mechanistically, our data showed that PRMT3 interacted with and mediated asymmetric dimethylarginine (ADMA) modification of lactate dehydrogenase A (LDHA) at arginine 112 (R112). Compared with LDHA-wild-type (LDHA-WT) cells, LDHA-R112K-mutant-expressing HCC cells exhibited a decrease in lactate dehydrogenase (LDH) activity, HCC cell glycolysis and proliferation. Furthermore, the administration of SGC707, a selective inhibitor of PRMT3, disrupted the PRMT3-mediated LDHA methylation and abolished PRMT3-induced HCC glycolysis and tumour growth.
CONCLUSIONS
Our results suggested a novel oncogenic role of PRMT3 in HCC, and it could be a promising therapeutic target for HCC by linking post-translational modification and cancer metabolism.
Topics: Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; China; Disease Models, Animal; Glycolysis; Histology; Humans; L-Lactate Dehydrogenase; Liver Neoplasms; Methylation; Mice; Protein-Arginine N-Methyltransferases
PubMed: 35090076
DOI: 10.1002/ctm2.686 -
Nature Communications Mar 2024Abundant macrophage infiltration and altered tumor metabolism are two key hallmarks of glioblastoma. By screening a cluster of metabolic small-molecule compounds, we...
Abundant macrophage infiltration and altered tumor metabolism are two key hallmarks of glioblastoma. By screening a cluster of metabolic small-molecule compounds, we show that inhibiting glioblastoma cell glycolysis impairs macrophage migration and lactate dehydrogenase inhibitor stiripentol emerges as the top hit. Combined profiling and functional studies demonstrate that lactate dehydrogenase A (LDHA)-directed extracellular signal-regulated kinase (ERK) pathway activates yes-associated protein 1 (YAP1)/ signal transducer and activator of transcription 3 (STAT3) transcriptional co-activators in glioblastoma cells to upregulate C-C motif chemokine ligand 2 (CCL2) and CCL7, which recruit macrophages into the tumor microenvironment. Reciprocally, infiltrating macrophages produce LDHA-containing extracellular vesicles to promote glioblastoma cell glycolysis, proliferation, and survival. Genetic and pharmacological inhibition of LDHA-mediated tumor-macrophage symbiosis markedly suppresses tumor progression and macrophage infiltration in glioblastoma mouse models. Analysis of tumor and plasma samples of glioblastoma patients confirms that LDHA and its downstream signals are potential biomarkers correlating positively with macrophage density. Thus, LDHA-mediated tumor-macrophage symbiosis provides therapeutic targets for glioblastoma.
Topics: Animals; Humans; Mice; Glioblastoma; L-Lactate Dehydrogenase; Lactate Dehydrogenase 5; Lactic Acid; Symbiosis; Tumor Microenvironment
PubMed: 38443336
DOI: 10.1038/s41467-024-46193-z -
European Journal of Cancer (Oxford,... Mar 2023Immunotherapies have significantly improved the survival of patients in many cancers over the last decade. However, primary and secondary resistances are encountered in... (Review)
Review
Immunotherapies have significantly improved the survival of patients in many cancers over the last decade. However, primary and secondary resistances are encountered in most patients. Unravelling resistance mechanisms to cancer immunotherapies is an area of active investigation. Elevated levels of circulating enzyme lactate dehydrogenase (LDH) have been historically considered in oncology as a marker of bad prognosis, usually attributed to elevated tumour burden and cancer metabolism. Recent evidence suggests that elevated LDH levels could be independent from tumour burden and contain a negative predictive value, which could help in guiding treatment strategies in immuno-oncology. In this review, we decipher the rationale supporting the potential of LDH-targeted therapeutic strategies to tackle the direct immunosuppressive effects of LDH on a wide range of immune cells, and enhance the survival of patients treated with cancer immunotherapies.
Topics: Humans; Immunotherapy; L-Lactate Dehydrogenase; Neoplasms; Prognosis
PubMed: 36657325
DOI: 10.1016/j.ejca.2022.11.032 -
Current Medicinal Chemistry 2019Lactate dehydrogenase (LHD) is a key enzyme of anaerobic metabolism in almost all living organisms and it is also a functional checkpoint for glucose restoration during... (Review)
Review
Lactate dehydrogenase (LHD) is a key enzyme of anaerobic metabolism in almost all living organisms and it is also a functional checkpoint for glucose restoration during gluconeogenesis and single-stranded DNA metabolism. This enzyme has a well preserved structure during evolution and among the species, with little, but sometimes very useful, changes in the amino acid sequence, which makes it an attractive target for the design and construction of functional molecules able to modulate its catalytic potential and expression. Research has focused mainly on the selection of modulator especially as far as LDH isozymes (especially LDH-5) and lactate dehydrogenases of Plasmodium falciparum (pfLDH) are concerned. This review summarizes the recent advances in the design and development of inhibitors, pointing out their specificity and therapeutic potentials.
Topics: Animals; Antimalarials; Azoles; Drug Discovery; Enzyme Inhibitors; Gossypol; Humans; Indoles; Isocoumarins; L-Lactate Dehydrogenase; Organic Chemicals; Plasmodium falciparum; Quinolines
PubMed: 28183261
DOI: 10.2174/0929867324666170209103444 -
International Journal of Radiation... Apr 2019The anaerobic metabolism of glucose by cancer cells, even under well-oxygenated conditions, has been documented by Otto Warburg as early as 1927. Micro-environmental... (Review)
Review
The anaerobic metabolism of glucose by cancer cells, even under well-oxygenated conditions, has been documented by Otto Warburg as early as 1927. Micro-environmental hypoxia and intracellular pathways activating the hypoxia-related gene response, shift cancer cell metabolism to anaerobic pathways. In the current review, we focus on a major enzyme involved in anaerobic transformation of pyruvate to lactate, namely lactate dehydrogenase 5 (LDH5). The value of LDH5 as a marker of prognosis of cancer patients, as a predictor of response to radiotherapy (RT) and chemotherapy and, finally, as a major target for cancer treatment and radio-sensitization is reported and discussed. Clinical, translational and experimental data supporting the uniqueness of the LDHA gene and its product LDH5 isoenzyme are summarized and future directions for a metabolic treatment of cancer are highlighted.
Topics: Anaerobiosis; Glucose; Humans; Isoenzymes; L-Lactate Dehydrogenase; Lactate Dehydrogenase 5; Neoplasms; Radiation Tolerance
PubMed: 29913092
DOI: 10.1080/09553002.2018.1490041 -
Clinical and Experimental Dermatology Jul 2020Lactate dehydrogenase (LDH) is used in dermatology practice, particularly as a prognostic marker for cutaneous lymphoma. LDH is an intracellular enzyme involved in... (Review)
Review
Lactate dehydrogenase (LDH) is used in dermatology practice, particularly as a prognostic marker for cutaneous lymphoma. LDH is an intracellular enzyme involved in anaerobic glycolysis, and is found at low concentrations in the blood. LDH is produced in every tissue, thus cell damage releases LDH into the circulation, so the causes of elevated LDH levels are multiple. The utility of LDH in dermatology practice is reviewed, alongside current diagnostic and staging guidelines.
Topics: Adolescent; Child; Child, Preschool; Dermatology; Disease Progression; Female; Humans; Infant; Infant, Newborn; L-Lactate Dehydrogenase; Lymphoma; Male; Melanoma; Neoplasm Staging; Reference Values; Skin Neoplasms
PubMed: 31755143
DOI: 10.1111/ced.14134