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Stoichiometric gene-to-reaction associations enhance model-driven analysis performance: Metabolic response to chronic exposure to Aldrin in prostate cancer

Authors: de Mas, Igor Marin; Torrents, Laura; Bedia, Carmen; Nielsen, Lars K.; Cascante, Marta; Tauler, Roma;

Stoichiometric gene-to-reaction associations enhance model-driven analysis performance: Metabolic response to chronic exposure to Aldrin in prostate cancer

Abstract

Genome-scale metabolic models (GSMM) integrating transcriptomics have been widely used to study cancer metabolism. This integration is achieved through logical rules that describe the association between genes, proteins, and reactions (GPRs). However, current gene-to-reaction formulation lacks the stoichiometry describing the transcript copies necessary to generate an active catalytic unit, which limits our understanding of how genes modulate metabolism. The present work introduces a new state-of-the-art GPR formulation that considers the stoichiometry of the transcripts (S-GPR). As case of concept, this novel gene-to-reaction formulation was applied to investigate the metabolic effects of the chronic exposure to Aldrin, an endocrine disruptor, on DU145 prostate cancer cells. To this aim we integrated the transcriptomic data from Aldrin-exposed and non-exposed DU145 cells through S-GPR or GPR into a human GSMM by applying different constraint-based-methods.Our study revealed a significant improvement of metabolite consumption/production predictions when S-GPRs are implemented. Furthermore, our computational analysis unveiled important alterations in carnitine shuttle and prostaglandine biosynthesis in Aldrin-exposed DU145 cells that is supported by bibliographic evidences of enhanced malignant phenotype.The method developed in this work enables a more accurate integration of gene expression data into model-driven methods. Thus, the presented approach is conceptually new and paves the way for more in-depth studies of aberrant cancer metabolism and other diseases with strong metabolic component with important environmental and clinical implications.

Countries
Denmark, Spain, Australia
Keywords

Male, QH426-470, Endocrine Disruptors, Models, Biological, Stoichiometric gene-protein-reaction association, Carnitine, Cell Line, Tumor, Genome-scale metabolic model, Genetics, Humans, /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being; name=SDG 3 - Good Health and Well-being, Transcriptomic data integration, Endocrine disruptors, Prostate cancer, Càncer de pròstata, Aldrin, Prostate Cancer, Computational Biology, Prostatic Neoplasms, 004, Lipidomics, Prostaglandins, Stoichiometric geneprotein-reaction association, Transcriptome, TP248.13-248.65, Metabolic Networks and Pathways, Biotechnology, Research Article

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selected citations
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This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
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