Inference of cancer mechanisms through computational systems analysis

Qi, Zhengjian; Voit, Eberhard O.

doi:10.1039/c6mb00672h

Cited by 16 publications

(13 citation statements)

References 25 publications

(27 reference statements)

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“…The relative importance of salvage versus de novo synthesis likely depend on the growth conditions and on the specific tissue. Recently it has ben argued that salvage pathways are very important in colorectal cancers for example, albeit without the assistance of isotope tracers (221). …”

Section: Stable Isotope Tracing Of Nucleotide Synthesismentioning

confidence: 99%

Regulation of mammalian nucleotide metabolism and biosynthesis

Lane

Fan

2015

Nucleic Acids Research

698

631

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Nucleotides are required for a wide variety of biological processes and are constantly synthesized de novo in all cells. When cells proliferate, increased nucleotide synthesis is necessary for DNA replication and for RNA production to support protein synthesis at different stages of the cell cycle, during which these events are regulated at multiple levels. Therefore the synthesis of the precursor nucleotides is also strongly regulated at multiple levels. Nucleotide synthesis is an energy intensive process that uses multiple metabolic pathways across different cell compartments and several sources of carbon and nitrogen. The processes are regulated at the transcription level by a set of master transcription factors but also at the enzyme level by allosteric regulation and feedback inhibition. Here we review the cellular demands of nucleotide biosynthesis, their metabolic pathways and mechanisms of regulation during the cell cycle. The use of stable isotope tracers for delineating the biosynthetic routes of the multiple intersecting pathways and how these are quantitatively controlled under different conditions is also highlighted. Moreover, the importance of nucleotide synthesis for cell viability is discussed and how this may lead to potential new approaches to drug development in diseases such as cancer.

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Section: Stable Isotope Tracing Of Nucleotide Synthesismentioning

confidence: 99%

Regulation of mammalian nucleotide metabolism and biosynthesis

Lane

Fan

2015

Nucleic Acids Research

698

631

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“…The relative importance of salvage versus de novo synthesis likely depends on the growth conditions and on the tissue specificity. Recently, it has been published that salvage pathways are very important for surviving and proliferation of cancer cells in colorectal cancers (Qi and Voit 2014).…”

Section: Discussionmentioning

confidence: 99%

DPYD genotype and haplotype analysis and colorectal cancer susceptibility in a case-control study from Slovakia

Matáková

Halašová²,

Škovierová³

et al. 2017

gpb

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Dihydropyrimidine dehydrogenase (DPD) acts as the first-step enzyme catabolizing pyrimidines in vivo. DPYD gene mutations interfere with the breakdown of uracil and thymine. Genetic variations of DPYD can cause an enzyme deficiency state, which results in severe toxicity or other adverse side effects such as DNA damage or RNA damage caused by imbalance of the nucleotide pool. Our case-control study investigates the possible association between seven DPYD gene polymophisms (rs1801267, rs72547602, rs1801160, rs3918290, rs1801159, rs1801158, rs1801265) and risk of colorectal cancer (CRC). The association analysis for DPD was performed on 273 CRC patients and 187 healthy controls. There is significant allele association of SNP rs1801160 with colorectal cancer (p = 0.003, OR = 3.264, 95% CI = 1.425-7.475) in present analysis. Haplotype analysis of four DPYD polymorphisms showed significant difference in the distribution "IISt" haplotype between cases and controls. In comparison to the most common haplotype (VISt), the "IISt" haplotype was associated with increased risk for CRC (p = 0.038, OR = 2.733, 95% CI = 1.019-7.326). The present study suggests that the SNP rs1801160 and the "IISt" haplotype in the DPYD gene may also have a role in colorectal cancer risk.

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“…The resulting flux models do not provide individual enzyme/transporter kinetics, nor can the model predict flux changes in response to perturbations of participant proteins. The KMA approaches require a full set of enzyme/ transporter kinetic parameters to solve sets of differential equations either at steady state, or under non-steady state conditions [165][166][167][168][169][170][171][172][173]. The models established provide individual enzymes/transporter kinetics and can predict how metabolic networks respond to changes in protein components.…”

Section: Informatics Needs For Pathway Mapping and Analysismentioning

confidence: 99%

NMR and MS-based Stable Isotope-Resolved Metabolomics and applications in cancer metabolism

Lane

Higashi

Fan

2019

TrAC Trends in Analytical Chemistry

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There is considerable interest in defining metabolic reprogramming in human diseases, which is recognized as a hallmark of human cancer. Although radiotracers have a long history in specific metabolic studies, stable isotope-enriched precursors coupled with modern high resolution mass spectrometry and NMR spectroscopy have enabled systematic mapping of metabolic networks and fluxes in cells, tissues and living organisms including humans. These analytical platforms are high in information content, are complementary and cross-validating in terms of compound identification, quantification, and isotope labeling pattern analysis of a large number of metabolites simultaneously. Furthermore, new developments in chemoselective derivatization and in vivo spectroscopy enable tracking of labile/low abundance metabolites and metabolic kinetics in real-time. Here we review developments in Stable Isotope Resolved Metabolomics (SIRM) and recent applications in cancer metabolism using a wide variety of stable isotope tracers that probe both broad and specific aspects of cancer metabolism required for proliferation and survival.

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Inference of cancer mechanisms through computational systems analysis

Cited by 16 publications

References 25 publications

Regulation of mammalian nucleotide metabolism and biosynthesis

Regulation of mammalian nucleotide metabolism and biosynthesis

DPYD genotype and haplotype analysis and colorectal cancer susceptibility in a case-control study from Slovakia

NMR and MS-based Stable Isotope-Resolved Metabolomics and applications in cancer metabolism

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