Triple Isozyme Lactic Acid Dehydrogenase Inhibition using GNE-140 in Fully Viable Breast Cancer Cells induces Cytostatic Effects which are not-reversed by exogenous Lactic Acid
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE189183 | GEO | 2021/11/20
REPOSITORIES: GEO
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Project description:Triple Isozyme Lactic Acid Dehydrogenase Inhibition using GNE-140 in Fully Viable Breast Cancer Cells induces Cytostatic Effects which are not-reversed by exogenous Lactic Acid
| PRJNA781855 | ENA
Project description:A number of aggressive human malignant tumors are characterized by an intensified glycolytic rate, over-expression of lactic acid dehydrogenase A (LDHA), and subsequent lactate accumulation, all of which contribute toward an acidic peri-cellular immunosuppressive tumor microenvironment (TME). While recent focus has been directed at how to inhibit LDHA, it is now becoming clear that multiple isozymes of LDH must be simultaneously inhibited in order to fully suppress lactic acid and halt glycolysis. In this work we explore the biochemical and genomic consequences of an applied triple LDH isozyme inhibitor (A, B, and C) (GNE-140) in MDA-MB-231 triple-negative breast cancer cells (TNBC) cells. The findings confirm that GNE-140 does in fact, fully block the production of lactic acid, which also results in a block of glucose utilization and severe impedance of the glycolytic pathway. Without a fully functional glycolytic pathway, breast cancer cells continue to thrive, sustain viability, produce ample energy, and maintain mitochondrial potential (ΔΨM). The only observable negative consequence of GNE-140 in this work, was the attenuation of cell division, evident in both 2D and 3D cultures and occurring in fully viable cells. Of important note, the cytostatic effects were not reversed by the addition of exogenous (+) lactic acid. While the effects of GNE-140 on the whole transcriptome were mild (12 up-regulated differential expressed genes (DEGs); 77 down-regulated DEGs) out of the 48,226 evaluated, the down-regulated DEGS collectively centered around a loss of genes related to mitosis, cell cycle, GO/G1-G1/S transition, and DNA replication. These data were also observed with digital florescence cytometry and flow cytometry, both corroborating a G0/G1 phase blockage. In conclusion, the findings in this work suggest there is an unknown element linking LDH enzyme activity to cell cycle progression, and this factor is completely independent of lactic acid. The data also establish that complete inhibition of LDH in cancer cells is not a detriment to cell viability or basic production of energy.
| S-EPMC8698706 | biostudies-literature
Project description:Early invasive growth and metastasis are features of pancreatic cancer that rely on resistance to anoikis, an apoptosis program activated upon loss of adequate matrix anchorage. Re-expression of the tumor suppressor p16 reversed anoikis resistance of pancreatic cancer cells. This conversion to an anoikis-susceptible phenotype was found to be associated with a striking loss of GNE mRNA expression, prompting us to address the role of GNE in pancreatic cancer in more detail. GNE catalyzes a rate-limiting key step of the sialic acid biosynthesis and may have additional functions in the nucleus. Pancreatic cancer cells Capan-1. Three GNE-silencing samples and three control samples.
2010-08-01 | E-GEOD-22336 | biostudies-arrayexpress
Project description:GNE myopathy is an adult onset neuromuscular disorder characterized by slowly progressive distal and proximal muscle weakness, caused by missense recessive mutations in the GNE gene. Although the encoded bifunctional enzyme is well known as the limiting factor in the biosynthesis of sialic acid, no clear mechanisms have been recognized to account for the muscle atrophic pathology, and novel functions for GNE have been hypothesized. Two major issues impair studies on this protein. First, the expression of the GNE protein is minimal in humans and mice muscles and there is no reliable antibody to follow up endogenous expression. Second, no reliable animal model is available for the disease and cellular models from GNE myopathy patients' muscle cells (expressing the mutated protein) are less informative than expected. In order to broaden our knowledge on GNE functions in muscle, we have taken advantage of the CRISPR/Cas9 method for genome editing to first, add a tag to the endogenous Gne gene in mouse, allowing the determination of the spatiotemporal expression of the protein in the organism using well established and reliable antibodies against the specific tag. In addition we have generated a Gne knock out murine muscle cell lineage to identify the events resulting from the total lack of the protein. A thorough multi-omics analysis of both systems including transcriptomics, proteomics, phosphoproteomics and ubiquitination, unraveled novel pathways for Gne, in particular its involvement in cell cycle control and in the DNA damage/repair pathway. The elucidation of fundamental mechanisms of Gne in normal muscle may contribute to the identification of the disrupted functions in GNE myopathy, thus, to the definition of novel biomarkers and possible therapeutic targets for this disease.
2023-03-10 | PXD033985 | Pride
Project description:GNE Myopathy is a rare, recessively inherited neuromuscular worldwide disorder, caused by a spectrum of bi-allelic mutations in the human GNE gene. GNE encodes a bi-functional enzyme responsible for the rate-limiting step of sialic acid biosynthesis pathway. However, the process in which GNE mutations lead to the development of a muscle pathology is not clear yet. Cellular and mouse models for GNE Myopathy established to date have not been informative. Further, additional GNE functions in muscle have been hypothesized. In these studies, we aimed to investigate gne functions using zebrafish genetic and transgenic models, and characterized them using macroscopic, microscopic, and molecular approaches. We first established transgenic zebrafish lineages expressing the human GNE cDNA carrying the M743T mutation, driven by the zebrafish gne promoter. These fish developed entirely normally. Then, we generated a gne knock-out (KO) fish using the CRISPR/Cas9 methodology. These fish died 8-10 days post-fertilization (dpf), but a phenotype appeared less than 24 hours before death and included progressive body axis curving, deflation of the swim bladder and decreasing movement and heart rate. However, muscle histology uncovered severe defects, already at 5 dpf, with compromised fiber organization. Sialic acid supplementation did not rescue the larvae from this phenotype nor prolonged their lifespan. To have deeper insights into the potential functions of gne in zebrafish, RNA sequencing was performed at 3 time points (3, 5, and 7 dpf). Genotype clustering was progressive, with only 5 genes differentially expressed in gne KO compared to gne WT siblings at 3 dpf. Enrichment analyses of the primary processes affected by the lack of gne also at 5 and 7 dpf point to the involvement of cell cycle and DNA damage/repair processes in the gne KO zebrafish. Thus, we have established a gne KO zebrafish lineage and obtained new insights into gne functions. This is the only model where GNE can be related to clear muscle defects, thus the only animal model relevant to GNE Myopathy to date. Further elucidation of gne precise mechanism-of-action in these processes could be relevant to GNE Myopathy and allow the identification of novel therapeutic targets.
2022-10-26 | GSE207593 | GEO
Project description:GNE myopathy is an adult onset neuromuscular disorder characterized by slowly progressive distal and proximal muscle weakness, caused by missense recessive mutations in the GNE gene. Although the encoded bifunctional enzyme is well known as the limiting factor in the biosynthesis of sialic acid, no clear mechanisms have been recognized to account for the muscle atrophic pathology, and novel functions for GNE have been hypothesized. No reliable animal model is available for the disease and cellular models from GNE myopathy patients' muscle cells (expressing the mutated protein) are less informative than expected. In order to broaden our knowledge on GNE functions in muscle, we have generated a Gne knock out murine muscle cell lineage to identify the events resulting from the total lack of the protein. A thorough multi-omics analysis of both systems including transcriptomics, proteomics, phosphoproteomics and ubiquitination, unraveled novel pathways for Gne, in particular its involvement in cell cycle control and in the DNA damage/repair pathway.The elucidation of fundamental mechanisms of Gne in normal muscle may contribute to the identification of the disrupted functions in GNE myopathy, thus, to the definition of novel biomarkers and possible therapeutic targets for this disease.
2022-10-26 | GSE202046 | GEO
Project description:Early invasive growth and metastasis are features of pancreatic cancer that rely on resistance to anoikis, an apoptosis program activated upon loss of adequate matrix anchorage. Re-expression of the tumor suppressor p16 reversed anoikis resistance of pancreatic cancer cells. This conversion to an anoikis-susceptible phenotype was found to be associated with a striking loss of GNE mRNA expression, prompting us to address the role of GNE in pancreatic cancer in more detail. GNE catalyzes a rate-limiting key step of the sialic acid biosynthesis and may have additional functions in the nucleus.
2010-08-01 | GSE22336 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE22334: Induction of apoptotic processes in Capan-1 pancreatic carcinoma cells by restoration of p16INK4a expression GSE22336: UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE) is an inducer of apoptotic processes in Capan-1 pancreatic carcinoma cells: GNE silencing Refer to individual Series
2010-08-01 | E-GEOD-22337 | biostudies-arrayexpress
Project description:ATAC-seq of H226 cells treated with TEAD inhibitor GNE-7884
2023-04-26 | GSE229064 | GEO
Project description:Molecular impacts in the pathogenesis of GNE myopathy in model mouse muscles were well described through expression profiling of a total of 34000 genes
2017-07-01 | GSE95150 | GEO