Oxamate, but Not Selective Targeting of LDH-A, Inhibits Medulloblastoma Cell Glycolysis, Growth and Motility

Valvona, Cara; Fillmore, Helen L.

doi:10.3390/brainsci8040056

Cited by 41 publications

(33 citation statements)

References 37 publications

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“…In cancer cells, LDHA helps in rapid conversion of pyruvate to lactate, minimizing pyruvate entry into TCA cycle in the mitochondria. High levels of LDHA helps cancer cells to establish and proliferate by promoting epithelial to mesenchymal transition [31], angiogenesis [15], cytoskeletal remodeling [32], increasing cell motility [33], invasion and migration [34]. One advantage of LDH-5 upregulation for cancer cells is to maintain fuel supply under hypoxic conditions and expectedly a broad range of highly invasive hypoxic cancers show high LDH-5 levels.…”

Section: Ldha In Cancersmentioning

confidence: 99%

Lactate Dehydrogenases as Metabolic Links between Tumor and Stroma in the Tumor Microenvironment

Mishra

Banerjee

2019

Cancers

200

156

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Cancer is a metabolic disease in which abnormally proliferating cancer cells rewire metabolic pathways in the tumor microenvironment (TME). Molecular reprogramming in the TME helps cancer cells to fulfill elevated metabolic demands for bioenergetics and cellular biosynthesis. One of the ways through which cancer cell achieve this is by regulating the expression of metabolic enzymes. Lactate dehydrogenase (LDH) is the primary metabolic enzyme that converts pyruvate to lactate and vice versa. LDH also plays a significant role in regulating nutrient exchange between tumor and stroma. Thus, targeting human lactate dehydrogenase for treating advanced carcinomas may be of benefit. LDHA and LDHB, two isoenzymes of LDH, participate in tumor stroma metabolic interaction and exchange of metabolic fuel and thus could serve as potential anticancer drug targets. This article reviews recent research discussing the roles of lactate dehydrogenase in cancer metabolism. As molecular regulation of LDHA and LDHB in different cancer remains obscure, we also review signaling pathways regulating LDHA and LDHB expression. We highlight on the role of small molecule inhibitors in targeting LDH activity and we emphasize the development of safer and more effective LDH inhibitors. We trust that this review will also generate interest in designing combination therapies based on LDH inhibition, with LDHA being targeted in tumors and LDHB in stromal cells for better treatment outcome.

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Section: Ldha In Cancersmentioning

confidence: 99%

Lactate Dehydrogenases as Metabolic Links between Tumor and Stroma in the Tumor Microenvironment

Mishra

Banerjee

2019

Cancers

200

156

View full text Add to dashboard Cite

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“…Hence, altered expression of LDHC could be involved in maintaining an alternative energy source by contributing to the metabolic switch in cancer cells. In addition, increased LDHA and decreased LDHB expressions facilitate tumor formation and progression through remodeling of the tumor microenvironment, increasing proliferation, and inducing epithelial-to-mesenchymal transition, cell migration and invasion, and angiogenesis [10][11][12][13][14][15][16][17][18][19][20]. In line with this, two studies to date demonstrate that enhanced expression of LDHC induces epithelial-to-mesenchymal transition, matrix metalloproteinase-9 (MMP9) expression and promotes cancer cell migration and invasion [7,21].…”

Section: Introductionmentioning

confidence: 81%

Identification of two HLA-A*0201 immunogenic epitopes of lactate dehydrogenase C (LDHC): potential novel targets for cancer immunotherapy

Thomas

Shaath

Belič

et al. 2020

Cancer Immunol Immunother

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Lactate dehydrogenase C (LDHC) is an archetypical cancer testis antigen with limited expression in adult tissues and reexpression in tumors. This restricted expression pattern together with the important role of LDHC in cancer metabolism renders LDHC a potential target for immunotherapy. This study is the first to investigate the immunogenicity of LDHC using T cells from healthy individuals. LDHC-specific T cell responses were induced by in vitro stimulation with synthetic peptides, or by priming with autologous peptide-pulsed dendritic cells. We evaluated T cell activation by IFN-γ ELISpot and determined cytolytic activity of HLA-A*0201-restricted T cells in breast cancer cell co-cultures. In vitro T cell stimulation induced IFN-γ secretion in response to numerous LDHC-derived peptides. Analysis of HLA-A*0201 responses revealed a significant T cell activation after stimulation with peptide pools 2 (PP2) and 8 (PP8). The PP2-and PP8-specific T cells displayed cytolytic activity against breast cancer cells with endogenous LDHC expression within a HLA-A*0201 context. We identified peptides LDHC 41−55 and LDHC 288−303 from PP2 and PP8 to elicit a functional cellular immune response. More specifically, we found an increase in IFN-γ secretion by CD8 + T cells and cancer-cell-killing of HLA-A*0201/LDHC positive breast cancer cells by LDHC 41−55-and LDHC 288−303-induced T cells, albeit with a possible antigen recognition threshold. The majority of induced T cells displayed an effector memory phenotype. To conclude, our findings support the rationale to assess LDHC as a targetable cancer testis antigen for immunotherapy, and in particular the HLA-A*0201 restricted LDHC 41-55 and LDHC 288-303 peptides within LDHC.

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“…The catalytic substrate of LDHA is competitively inhibited by oxamate, a pyruvate analog, and its effect has been identified in various cell lines (15,(37)(38)(39). A study by Zhao et al (15) demonstrated that oxamate inhibited the activity of gastric cancer cells in a dose-and time-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

LDHA Promotes Oral Squamous Cell Carcinoma Progression Through Facilitating Glycolysis and Epithelial–Mesenchymal Transition

Cai

Zhang

et al. 2019

Front. Oncol.

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Aerobic glycolysis is the main pathway for energy metabolism in cancer cells. It provides energy and biosynthetic substances for tumor progression and metastasis by increasing lactate production. Lactate dehydrogenase A (LDHA) promotes glycolysis process by catalyzing the conversion of pyruvate to lactate. Despite LDHA exhibiting carcinogenesis in various cancers, its role in oral squamous cell carcinoma (OSCC) remains unclear. This study demonstrated that LDHA was over-expressed in both OSCC tissues and cell lines, and was significantly associated with lower overall survival rates in patients with OSCC. Using weighted gene correlation network analysis and gene set enrichment analysis for the gene expression data of patients with OSCC (obtained from The Cancer Genome Atlas database), a close association was identified between epithelial-mesenchymal transition (EMT) and LDHA in promoting OSCC progression. The knockdown of LDHA suppressed EMT, cell proliferation, and migration and invasion of OSCC cells in vitro. Moreover, the silencing of LDHA inhibited tumor growth in vivo. Oxamate, as a competitive LDHA inhibitor, was also suppressed diverse malignant biocharacteristics of OSCC cells. Our findings reveal that LDHA acts as an oncogene to promote malignant progression of OSCC by facilitating glycolysis and EMT, and LDHA may be a potential anticancer therapeutic target.

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Oxamate, but Not Selective Targeting of LDH-A, Inhibits Medulloblastoma Cell Glycolysis, Growth and Motility

Cited by 41 publications

References 37 publications

Lactate Dehydrogenases as Metabolic Links between Tumor and Stroma in the Tumor Microenvironment

Lactate Dehydrogenases as Metabolic Links between Tumor and Stroma in the Tumor Microenvironment

Identification of two HLA-A*0201 immunogenic epitopes of lactate dehydrogenase C (LDHC): potential novel targets for cancer immunotherapy

LDHA Promotes Oral Squamous Cell Carcinoma Progression Through Facilitating Glycolysis and Epithelial–Mesenchymal Transition

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