Data, information, knowledge and principle: back to metabolism in KEGG

Exogenous glutamine is an important source of energy and molecular building blocks for many tumors. There is a renewed interest in therapeutically targeting glutamine metabolism due to the recent discovery of two novel glutaminase inhibitors. To quantify the dysregulation of the glutamate-glutamine equilibrium in breast cancer, metabolomics analysis of 270 clinical breast cancer samples and 97 normal breast samples was carried out using gas chromatography combined with time-of-flight mass spectrometry. Positive correlation between glutamate and glutamine in normal breast tissues switched to negative correlation between glutamate and glutamine in breast cancer tissues. Compared with the ratio of glutamate to glutamine in normal tissues, we found 56% of the ER1 tumor tissues and 88% of the ER2 tumor tissues glutamate-enriched. The glutamateto-glutamine ratio (GGR) significantly correlated with ER status (p 5 8.0E-09) and with tumor grade (p 5 3.3E-05). Higher levels of GGR were associated with prolonged overall survival in univariate analysis (HR 5 0.77, p 5 0.027) and in multivariate analysis (HR 5 0.73, p 5 0.038). GGR levels were reflected in an unsupervised clustering of metabolomics profiles. In a supervised analysis of metabolomics data and of genome-wide expression data, replacement of GGR by metabolite surrogate markers was feasible, while replacement of GGR by RNA markers had a limited accuracy. Functional analysis of the gene expression data showed negative correlation between glutamate enrichment and activation of peroxisome proliferator-activated receptor (PPAR) pathway. Our findings may have important implications for patient stratification related to utilization of glutaminase inhibitors.Altered energy metabolism is acknowledged as one of the emerging hallmarks of cancer. 1 Recently, there is a renewed interest in the metabolic transformation occurring in cancer cells and in targeting metabolic enzymes for cancer therapy. 2-4 However, the discovery of dysregulated metabolism in tumors dates back to the work of Otto Warburg in the 1920s. Warburg observed that cancer cells exhibit elevated glycolysis and that much of the generated pyruvate is fermented to lactate rather than feed to the TCA cycle and used for oxidative phosphorylation. 5,6 This phenomenon occurs under anaerobic and even under aerobic conditions ("aerobic glycolysis").A second change that occurs in central metabolism of many cancer cells is the alteration of glutamine metabolism. 7-9 Glutamine can be used to replenish the TCA cycle instead of glucose and feed in carbon and nitrogen for synthesis of nucleotides, several amino acids and glutathione. Further, glutamine can be used for energy production and in transformed cultured cells glutamine driven oxidative phosphorylation was recently shown to be the main source of

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“…The regulated genes in the PPAR pathway were visualized using the mapper interface on the webpage of the KEGG database. 27 …”

Section: Resultsmentioning

confidence: 99%

Glutamate enrichment as new diagnostic opportunity in breast cancer

Budczies

Pfitzner

Győrffy

et al. 2014

Intl Journal of Cancer

110

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“…The genes that overlapped with DMR were then input into the KEGG pathway search [69,70] to identify associated pathways. The DMR associated genes were then sorted into functional groups by consulting information provided by the DAVID [71], Panther [72], and Uniprot databases incorporated into an internal curated database (www.skinner.wsu.edu under genomic data).…”

Section: Methodsmentioning

confidence: 99%

Environmental toxicant induced epigenetic transgenerational inheritance of ovarian pathology and granulosa cell epigenome and transcriptome alterations: ancestral origins of polycystic ovarian syndrome and primary ovarian insufficiency

et al. 2018

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Two of the most prevalent ovarian diseases affecting women’s fertility and health are Primary Ovarian Insufficiency (POI) and Polycystic Ovarian Syndrome (PCOS). Previous studies have shown that exposure to a number of environmental toxicants can promote the epigenetic transgenerational inheritance of ovarian disease. In the current study, transgenerational changes to the transcriptome and epigenome of ovarian granulosa cells are characterized in F3 generation rats after ancestral vinclozolin or DDT exposures. In purified granulosa cells from 20-day-old F3 generation females, 164 differentially methylated regions (DMRs) (P < 1 x 10−6) were found in the F3 generation vinclozolin lineage and 293 DMRs (P < 1 x 10−6) in the DDT lineage, compared to controls. Long noncoding RNAs (lncRNAs) and small noncoding RNAs (sncRNAs) were found to be differentially expressed in both the vinclozolin and DDT lineage granulosa cells. There were 492 sncRNAs (P < 1 x 10−4) in the vinclozolin lineage and 1,085 sncRNAs (P < 1 x 10−4) in the DDT lineage. There were 123 lncRNAs and 51 lncRNAs in the vinclozolin and DDT lineages, respectively (P < 1 x 10−4). Differentially expressed mRNAs were also found in the vinclozolin lineage (174 mRNAs at P < 1 x 10−4) and the DDT lineage (212 mRNAs at P < 1 x 10−4) granulosa cells. Comparisons with known ovarian disease associated genes were made. These transgenerational epigenetic changes appear to contribute to the dysregulation of the ovary and disease susceptibility that can occur in later life. Observations suggest that ancestral exposure to toxicants is a risk factor that must be considered in the molecular etiology of ovarian disease.

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“…Salmonella analyses: A database of pathways, regulons, and genomic islands was constructed using information obtained from the KEGG database (Kanehisa et al, 2014) (organism code sey), the SL1344 genome annotation Human analyses: A transcript was considered to be detected if in at least one condition the observed RPKM was above 0.1 for lncRNA genes and 0.5 for all other human transcript classes, respectively. For a given comparison, all detected transcripts showing at least a 1.5 fold-change in abundance and a p-value below 0.01 were considered differentially expressed.…”

Section: Rna-seq Techniquesmentioning

confidence: 99%

Dual RNA-seq of pathogen and host

2012

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SummaryThe infection of a eukaryotic host cell by a bacterial pathogen is one of the most intimate examples of cross-kingdom interactions in biology. Infection processes are highly relevant from both a basic research as well as a clinical point of view. Sophisticated mechanisms have evolved in the pathogen to manipulate the host response and vice versa host cells have developed a wide range of anti-microbial defense strategies to combat bacterial invasion and clear infections.However, it is this diversity and complexity that makes infection research so challenging to technically address as common approaches have either been optimized for bacterial or eukaryotic organisms. Instead, methods are required that are able to deal with the often dramatic discrepancy between host and pathogen with respect to various cellular properties and processes. One class of cellular macromolecules that exemplify this host-pathogen heterogeneity is given by their transcriptomes: Bacterial transcripts differ from their eukaryotic counterparts in many aspects that involve both quantitative and qualitative traits. The entity of RNA transcripts present in a cell is of paramount interest as it reflects the cell's physiological state under the given condition. Genome-wide transcriptomic techniques such as RNA-seq have therefore been used for single-organism analyses for several years, but their applicability has been limited for infection studies.The present work describes the establishment of a novel transcriptomic approach for infection biology which we have termed "Dual RNA-seq". Using this technology, it was intended to shed light particularly on the contribution of non-protein-encoding transcripts to virulence, as these classes have mostly evaded previous infection studies due to the lack of suitable methods. The performance of Dual RNA-seq was evaluated in an in vitro infection model based on the important facultative intracellular pathogen Salmonella enterica serovar Typhimurium and different human cell lines. Dual RNA-seq was found to be capable of capturing all major bacterial and human transcript classes and proved reproducible. During the course of these experiments, a previously largely uncharacterized bacterial small non-coding RNA (sRNA), referred to as STnc440, was identified as one of the most strongly induced genes in intracellular Salmonella.Interestingly, while inhibition of STnc440 expression has been previously shown to cause a virulence defect in different animal models of Salmonellosis, the underlying molecular mechanisms have remained obscure. Here, classical genetics, transcriptomics and biochemical assays proposed a complex model of Salmonella gene expression control that is orchestrated by this sRNA. In particular, STnc440 was found to be involved in the regulation of multiple bacterial target mRNAs by direct base pair interaction with consequences for Salmonella virulence and

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Data, information, knowledge and principle: back to metabolism in KEGG

Cited by 2,754 publications

References 6 publications

Glutamate enrichment as new diagnostic opportunity in breast cancer

Glutamate enrichment as new diagnostic opportunity in breast cancer

Environmental toxicant induced epigenetic transgenerational inheritance of ovarian pathology and granulosa cell epigenome and transcriptome alterations: ancestral origins of polycystic ovarian syndrome and primary ovarian insufficiency

Dual RNA-seq of pathogen and host

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