Role of LDH in tumor glycolysis: Regulation of LDHA by small molecules for cancer therapeutics

Sharma, Dolly; Singh, Mamta; Rani, Reshma

doi:10.1016/j.semcancer.2022.11.007

Cited by 122 publications

(59 citation statements)

References 100 publications

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“…For instance, some studies have reported that lactate dehydrogenase (LDH) is upregulated after cell cancerization. Following this concept, the upregulation of LDH may be more inclined to the increasing level of glycolysis, and related research and treatment will also be inclined to it [ 125 , 126 ]. However, later studies indicated that high levels of LDH did not cause the accumulation of lactic acid and extracellular acids [ 127 ].…”

Section: Metabolic Plasticity In the Initiation Of Tumourigenesismentioning

confidence: 99%

Regulative Roles of Metabolic Plasticity Caused by Mitochondrial Oxidative Phosphorylation and Glycolysis on the Initiation and Progression of Tumorigenesis

Niu

et al. 2023

IJMS

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One important feature of tumour development is the regulatory role of metabolic plasticity in maintaining the balance of mitochondrial oxidative phosphorylation and glycolysis in cancer cells. In recent years, the transition and/or function of metabolic phenotypes between mitochondrial oxidative phosphorylation and glycolysis in tumour cells have been extensively studied. In this review, we aimed to elucidate the characteristics of metabolic plasticity (emphasizing their effects, such as immune escape, angiogenesis migration, invasiveness, heterogeneity, adhesion, and phenotypic properties of cancers, among others) on tumour progression, including the initiation and progression phases. Thus, this article provides an overall understanding of the influence of abnormal metabolic remodeling on malignant proliferation and pathophysiological changes in carcinoma.

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Section: Metabolic Plasticity In the Initiation Of Tumourigenesismentioning

confidence: 99%

Regulative Roles of Metabolic Plasticity Caused by Mitochondrial Oxidative Phosphorylation and Glycolysis on the Initiation and Progression of Tumorigenesis

Niu

et al. 2023

IJMS

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“…LDHA, a subtype of LDH, has been demonstrated to have excellent anticancer activities. Inhibition of LDHA enhances the sensitivity of cancer cells to chemotherapy, while suppressing cell proliferation, invasion, and epithelial‐to‐mesenchymal transition (EMT) 44,70 . Transcription factors like c‐myc, HIF‐1, and p53 can inhibit LDHA activity, exerting anti‐tumor effects 44 .…”

Section: Discussionmentioning

confidence: 99%

Genetically predicted 486 blood metabolites in relation to risk of colorectal cancer: A Mendelian randomization study

Yun

Guo

et al. 2023

Cancer Medicine

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Background Metabolic disorders are a hallmark feature of cancer. However, the evidence for the causality of circulating metabolites to promote or prevent colorectal cancer (CRC) is still lacking. We performed a two‐sample Mendelian randomization (MR) analysis to assess the causality from genetically proxied 486 blood metabolites to CRC. Methods Genome‐wide association study (GWAS) data for exposures were extracted from 7824 Europeans GWAS on metabolite levels. GWAS data for CRC from the GWAS catalog database GCST012879 were used for the preliminary analysis. The random inverse variance weighted (IVW) is the primary analysis for causality analysis while MR‐Egger and weighted median as complementary analyses. Cochran Q test, MR‐Egger intercept test, MR‐PRESSO, Radial MR, and leave‐one‐out analysis were used for sensitivity analyses. For significant associations, additional independent CRC GWAS data GCST012880 were used for replication analysis and meta‐analysis. For the final identification of metabolites, Steiger test, linkage disequilibrium score regression, and colocalization analysis were performed for further evaluation. Multivariable MR was performed to assess the direct effect of metabolites on CRC. Results The results of this study indicated significant associations between six metabolites pyruvate (odds ratio [OR]: 0.49, 95% confidence interval [CI]: 0.32–0.77, p = 0.002), 1,6‐anhydroglucose (OR: 1.33, 95% CI: 1.11–1.59, p = 0.002), nonadecanoate (19:0) (OR: 0.40, 95% C I:0.4–0.68, p = 0.0008), 1‐linoleoylglycerophosphoethanolamine (OR: 0.47, 95% CI: 0.30–0.75, p = 0.001), 2‐hydroxystearate (OR: 0.39, 95% CI: 0.23–0.67, p = 0.0007), gamma‐glutamylthreonine (OR: 2.14, 95% CI: 1.02–4.50, p = 0.040) and CRC. MVMR analysis revealed that genetically predicted pyruvate, 1‐linoleoylglycerophosphoethanolamine and gamma‐glutamylthreonine can directly influence CRC independently of other metabolites. Conclusion The current work provides evidence to support the causality of the six circulating metabolites on CRC and a new perspective on the exploration of the biological mechanisms of CRC by combining genomics and metabolomics. These findings contribute to the screening, prevention and treatment of CRC.

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“…LDH-A is a key enzyme that is responsible for the conversion of pyruvate to lactate in the glycolytic pathway [6, 7]. This forward reaction facilitates cancer cells by increasing glucose uptake, extracellular acidification, and intracellular ATP levels [52]. Many reports have suggested that inhibition of LDH-A is responsible for lowering the glycolytic flux [52, 53].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Lactate Dehydrogenase A (LDH-A) by Diclofenac Sodium Induces Apoptosis in HeLa Cells by Activation of AMPK

Malla,

Gupta,

Sur

2023

Preprint

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Cancer cells exhibit a unique metabolic preference for choosing the glycolytic pathway over oxidative phosphorylation for maintaining the tumor microenvironment. Lactate dehydrogenase-A (LDH-A) is a key enzyme that facilitates glycolysis by converting pyruvate to lactate and has been shown to be upregulated in multiple cancers due to the hypoxic tumor microenvironment. Diclofenac (DCF), a non-steroidal anti-inflammatory drug, has been shown to exhibit anti-cancer effects by interfering with the glucose metabolism pathway. However, the specific targets remain unknown. Usingin-silico, biochemical, and biophysical studies, we show that DCF binds to LDH-A adjacent to the substrate binding site and dose-dependently inhibits its activity in an allosteric manner in HeLa cells. Thus, DCF inhibits the hypoxic microenvironment and induces apoptosis-mediated cell death. DCF fails to induce cytotoxicity in LDH-A knocked-down HeLa cells, confirming that DCF renders its anti-mitotic effects via LDH-A inhibition. DCF-induced LDH-A inhibition alters pyruvate, lactate, NAD+, and ATP production in cells, and this could be a possible mechanism by which DCF inhibits glucose uptake in cancer cells. DCF-induced ATP deprivation leads to mitochondria-mediated oxidative stress, which results in DNA damage, lipid peroxidation, and apoptosis-mediated cell death. Reduction in intracellular ATP levels additionally activates AMPK, a sensor kinase, which further downregulates p-S6K, leading to apoptosis-mediated cell death. We find that in LDH-A knocked-down cells, intracellular ATP levels were depleted, resulting in the inhibition of p-S6K, implying the involvement of DCF-induced LDH-A inhibition in the activation of the AMPK/S6K signaling pathway.

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Role of LDH in tumor glycolysis: Regulation of LDHA by small molecules for cancer therapeutics

Cited by 122 publications

References 100 publications

Regulative Roles of Metabolic Plasticity Caused by Mitochondrial Oxidative Phosphorylation and Glycolysis on the Initiation and Progression of Tumorigenesis

Regulative Roles of Metabolic Plasticity Caused by Mitochondrial Oxidative Phosphorylation and Glycolysis on the Initiation and Progression of Tumorigenesis

Genetically predicted 486 blood metabolites in relation to risk of colorectal cancer: A Mendelian randomization study

Inhibition of Lactate Dehydrogenase A (LDH-A) by Diclofenac Sodium Induces Apoptosis in HeLa Cells by Activation of AMPK

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