GPD1 enhances the anti-cancer effects of metformin by synergistically increasing total cellular glycerol-3-phosphate
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE146982 | GEO | 2020/03/15
REPOSITORIES: GEO
Similar Datasets
Project description:GPD1 enhances the anti-cancer effects of metformin by synergistically increasing total cellular glycerol-3-phosphate
| PRJNA612620 | ENA
Project description:Cancer stem cells (CSCs) are attractive targets for cancer therapy, however, little is known about how to target CSCs without affecting the normal stem cell population. Here we report the ribosome-profiling analysis of mouse neural stem cells and brain tumour stem cells (BTSCs), which leads to the identification of glycerol-3-phosphate dehydrogenase 1 (GPD1) as a CSC- specific determinant. We confirmed that GPD1 is expressed in BTSCs but not in neural stem cells. Intriguingly, expression of GPD1 is only found in the infiltrating dormant BTSCs in vivo and these cells start to divide and drive tumour relapse after chemotherapy. Most importantly, inhibition of GPD1 expression in tumour-bearing mice leads to prolonged survival. Further analysis shows that loss of GPD1 results in widespread changes in important pathways affecting BTSC maintenance. Human patient data analysis suggests that GPD1 is expressed in the dormant infiltrating tumour cells in human glioblastoma and the expression level is associated with a worse prognosis. This study provides an attractive therapeutic target for treating brain tumours and a novel aspect of regulation of CSC dormancy.
2019-07-15 | GSE110868 | GEO
Project description:The interconversion of glycerol 3-phosphate and dihydroxyacetone phosphate by glycerol-3-phosphate dehydrogenases provides a link between carbohydrate and lipid metabolism and provides Saccharomyces cerevisiae with protection against osmotic and anoxic stress. The first structure of a glycerol-3-phosphate dehydrogenase from S. cerevisiae, GPD1, is reported at 2.45?Å resolution. The asymmetric unit contains two monomers, each of which is organized with N- and C-terminal domains. The N-terminal domain contains a classic Rossmann fold with the (?-?-?-?-?)2 motif typical of many NAD+-dependent enzymes, while the C-terminal domain is mainly ?-helical. Structural and phylogenetic comparisons reveal four main structure types among the five families of glycerol-3-phosphate and glycerol-1-phosphate dehydrogenases and reveal that the Clostridium acetobutylican protein with PDB code 3ce9 is a glycerol-1-phosphate dehydrogenase.
| S-EPMC3515364 | biostudies-literature
Project description:Metformin rejuvenates adult rat oligodendrocyte progenitor cells (OPCs) allowing more efficient differentiation into oligodendrocytes and improved remyelination of CNS axons and therefore is of interest as a possible therapeutic in demyelinating diseases such as multiple sclerosis (MS). We set out to test whether metformin had a similar effect in human stem cell derived-OPCs. We assessed the suitability of human monoculture, organoid and transplantation into immunodeficient mice (chimera model) culture systems in simulating in vivo adult human oligodendrocytes, finding most close resemblance in the chimera model. Metformin increased myelin proteins and/or sheaths in all models even when human cells had fetal signatures. In the chimera model, metformin led to a marked increase in mitochondrial area both in the human transplanted cells and in the mouse axons with associated increase in transcripts related to mitochondrial function and metabolism. Human oligodendrocytes from MS brain donors treated pre-mortem with metformin also expressed similar transcripts suggesting that metformin’s brain effect is not cell-specific, altering metabolism in both oligodendrocytes and axons leading to more myelin production, in part through mitochondrial changes. This bodes well for ongoing clinical trials testing metformin for neuroprotection.
2024-12-10 | GSE282369 | GEO
Project description:Cancer stem cells (CSCs) are attractive targets for cancer therapy, however, little is known about how to target CSCs without affecting the normal stem cell population. Here we report the ribosome-profiling analysis of mouse neural stem cells and brain tumour stem cells (BTSCs), which leads to the identification of glycerol-3-phosphate dehydrogenase 1 (GPD1) as a CSC- specific determinant. We confirmed that GPD1 is expressed in BTSCs but not in neural stem cells. Intriguingly, expression of GPD1 is only found in the infiltrating dormant BTSCs in vivo and these cells start to divide and drive tumour relapse after chemotherapy. Most importantly, inhibition of GPD1 expression in tumour-bearing mice leads to prolonged survival. Further analysis shows that loss of GPD1 results in widespread changes in important pathways affecting BTSC maintenance. Human patient data analysis suggests that GPD1 is expressed in the dormant infiltrating tumour cells in human glioblastoma and the expression level is associated with a worse prognosis. This study provides an attractive therapeutic target for treating brain tumours and a novel aspect of regulation of CSC dormancy.
2019-07-15 | GSE110866 | GEO
Project description:Cancer stem cells (CSCs) are attractive targets for cancer therapy, however, little is known about how to target CSCs without affecting the normal stem cell population. Here we report the ribosome-profiling analysis of mouse neural stem cells and brain tumour stem cells (BTSCs), which leads to the identification of glycerol-3-phosphate dehydrogenase 1 (GPD1) as a CSC- specific determinant. We confirmed that GPD1 is expressed in BTSCs but not in neural stem cells. Intriguingly, expression of GPD1 is only found in the infiltrating dormant BTSCs in vivo and these cells start to divide and drive tumour relapse after chemotherapy. Most importantly, inhibition of GPD1 expression in tumour-bearing mice leads to prolonged survival. Further analysis shows that loss of GPD1 results in widespread changes in important pathways affecting BTSC maintenance. Human patient data analysis suggests that GPD1 is expressed in the dormant infiltrating tumour cells in human glioblastoma and the expression level is associated with a worse prognosis. This study provides an attractive therapeutic target for treating brain tumours and a novel aspect of regulation of CSC dormancy.
2019-07-15 | GSE110867 | GEO
Project description:The molecular basis for primary hereditary hypertriglyceridemia has been identified in fewer than 5% of cases. Investigation of monogenic dyslipidemias has the potential to expose key metabolic pathways. We describe a hitherto unreported disease in ten individuals manifesting as moderate to severe transient childhood hypertriglyceridemia and fatty liver followed by hepatic fibrosis and the identification of the mutated gene responsible for this condition. We performed SNP array-based homozygosity mapping and found a single large continuous segment of homozygosity on chromosomal region 12q13.12. The candidate region contained 35 genes that are listed in Online Mendelian Inheritance in Man (OMIM) and 27 other genes. We performed candidate gene sequencing and screened both clinically affected individuals (children and adults with hypertriglyceridemia) and also a healthy cohort for mutations in GPD1, which encodes glycerol-3-phosphate dehydrogenase 1. Mutation analysis revealed a homozygous splicing mutation, c.361-1G>C, which resulted in an aberrantly spliced mRNA in the ten affected individuals. This mutation is predicted to result in a truncated protein lacking essential conserved residues, including a functional site responsible for initial substrate recognition. Functional consequences of the mutation were evaluated by measuring intracellular concentrations of cholesterol and triglyceride as well as triglyceride secretion in HepG2 (hepatocellular carcinoma) human cells lines overexpressing normal and mutant GPD1 cDNA. Overexpression of mutant GPD1 in HepG2 cells, in comparison to overexpression of wild-type GPD1, resulted in increased secretion of triglycerides (p = 0.01). This finding supports the pathogenicity of the identified mutation.
| S-EPMC3257852 | biostudies-literature
Project description:Metformin is one of the first-line drugs for clinical treatment of type II diabetes, and recent studies have found that metformin can inhibit the development of multiple malignant tumors. When metformin is combined with chemotherapeutic drugs to treat head and neck squamous cell carcinoma（HNSCC）, it can effectively enhance the efficacy of chemotherapy. The aim of this study was to define the signaling pathways regulated by metformin in HNSCC, and the underlying mechanisms by which metformin sensitizes HNSCC chemotherapy. We used RNA sequencing (RNA-seq) to examine metformin regulated genes in the cal27, human tongue squamous carcinoma cell line, using RT-PCR to determine alterations in gene expression. Data from RNA-seq analysis showed that gene products involved in DNA replication, cell cycle, IL-17 signaling pathway, mismatch repair were all regulated by metformin. Our results suggest that metformin regulates multiple pathways associated with tumor growth and progression in HNSCC.
2022-07-03 | GSE207122 | GEO
Project description:BackgroundBrugada syndrome is a rare, autosomal-dominant, male-predominant form of idiopathic ventricular fibrillation characterized by a right bundle-branch block and ST elevation in the right precordial leads of the surface ECG. Mutations in the cardiac Na+ channel SCN5A on chromosome 3p21 cause approximately 20% of the cases of Brugada syndrome; most mutations decrease inward Na+ current, some by preventing trafficking of the channels to the surface membrane. We previously used positional cloning to identify a new locus on chromosome 3p24 in a large family with Brugada syndrome and excluded SCN5A as a candidate gene.Methods and resultsWe used direct sequencing to identify a mutation (A280V) in a conserved amino acid of the glycerol-3-phosphate dehydrogenase 1-like (GPD1-L) gene. The mutation was present in all affected individuals and absent in >500 control subjects. GPD1-L RNA and protein are abundant in the heart. Compared with wild-type GPD1-L, coexpression of A280V GPD1-L with SCN5A in HEK cells reduced inward Na+ currents by approximately 50% (P<0.005). Wild-type GPD1-L localized near the cell surface to a greater extent than A280V GPD1-L. Coexpression of A280V GPD1-L with SCN5A reduced SCN5A cell surface expression by 31+/-5% (P=0.01).ConclusionsGPD1-L is a novel gene that may affect trafficking of the cardiac Na+ channel to the cell surface. A GPD1-L mutation decreases SCN5A surface membrane expression, reduces inward Na+ current, and causes Brugada syndrome.
| S-EPMC3150966 | biostudies-literature
Project description:Metformin is the therapy of choice for treating type 2 diabetes and is currently repurposed for a wide range of diseases including aging. Recent evidence implicates the gut microbiota as a site of metformin action. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we performed C. elegans RNAseq to investigate the role of the metformin sensitive OP50 and metformin resistant OP50-MR E. coli microbiota in the drug effects on the host. Our data suggest an evolutionarily conserved bacterial mediation of metformin effects on host lipid metabolism and lifespan.
2019-07-13 | E-MTAB-7272 | biostudies-arrayexpress