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GNPS - Butyrate Suppresses Proliferation of Colon Cancer Cells via Targeting Pyruvate Kinase M2 and Metabolic Reprogramming

ABSTRACT: How butyrate interrupts the metabolism of cancer cells and leads to the suppression of cell proliferation remains unclear. We employed a metabolomics-proteomics combined approach to explore the link between butyrate-mediated proliferation arrest and cell metabolism. Metabolomics study revealed a remodeled metabolic profile with pronounced accumulation of pyruvate. A proteomics-based approach reveals PKM2 as a direct target of butyrate. it activates PKM2 via promoting its dephosphorylation and tetramerization.Our study provides a mechanistic link between PKM2-induced metabolic remodeling and the anti-tumorigenic function of butyrate.

INSTRUMENT(S): MALDI Synapt G2-S HDMS

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Hui Ye

PROVIDER: MSV000082189 | GNPS | Wed Mar 21 02:33:00 GMT 2018

REPOSITORIES: GNPS

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Butyrate Suppresses Proliferation of Colon Cancer Cells via Targeting Pyruvate Kinase M2 and Metabolic Reprogramming

Project description:How butyrate interrupts the metabolism of cancer cells and leads to the suppression of cell proliferation remains unclear. We employed a metabolomics-proteomics combined approach to explore the link between butyrate-mediated proliferation arrest and cell metabolism. Metabolomics study revealed a remodeled metabolic profile with pronounced accumulation of pyruvate. A proteomics-based approach reveals PKM2 as a direct target of butyrate. it activates PKM2 via promoting its dephosphorylation and tetramerization.Our study provides a mechanistic link between PKM2-induced metabolic remodeling and the anti-tumorigenic function of butyrate.

2018-03-21 | MSV000082189 | MassIVE

Targeted inhibition of ubiquitin signaling reverses the metabolic reprogramming and suppresses Glioblastoma growth

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Fibroblast-specific genome-scale modelling predicts an imbalance in amino acid metabolism in Refsum disease

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Metabolic reprogramming by Acly inhibition using SB-204990 alters glucoregulation and modulates molecular mechanisms associated with aging

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Gut-derived short-chain fatty acids are vividly assimilated into host carbohydrates and lipids

Project description:Acetate, propionate and butyrate are the main short-chain fatty acids (SCFAs) that arise from the fermentation of fibers by the colonic microbiota. While many studies focus on the regulatory role of SCFAs, their quantitative role as a catabolic or anabolic substrate for the host has received relatively little attention. To investigate this aspect, we infused conscious mice with physiological quantities of stable isotopes [1-13C]acetate, [2-13C]propionate or [2,4-13C2]butyrate directly into the cecum, which is the natural production site in mice, and analyzed their interconversion by the microbiota as well as their metabolism by the host. Cecal interconversion - pointing to microbial cross-feeding - was high between acetate and butyrate, low between butyrate and propionate and almost absent between acetate and propionate. As much as 62% of infused propionate was used in whole-body glucose production, in line with its role as gluconeogenic substrate. Conversely, glucose synthesis from propionate accounted for 69% of total glucose production. The synthesis of palmitate and cholesterol in the liver was high from cecal acetate (2.8% and 0.7%, respectively) and butyrate (2.7% and 0.9%, respectively) as substrates, but low or absent from propionate (0.6% and 0.0%, respectively). Label incorporation due to chain elongation of stearate was approximately 8-fold higher than de novo synthesis of stearate. Microarray data suggested that SCFAs exert only a mild regulatory effect on the expression of genes involved in hepatic metabolic pathways during the 6h infusion period. Altogether, gut-derived acetate, propionate and butyrate play important roles as substrates for glucose, cholesterol and lipid metabolism. Mice were infused in cecum with stably-labelled isotopes of the three main short chain fatty acids or control solution. After 6 hrs, livers were removed and pooled RNA samples were subjected to gene expression profiling.

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Butyrate protects pancreatic beta cells from cytokine induced dysfunction

Project description:Beta cell dysfunction, caused by metabolic and inflammatory stress, contributes to the development of type 2 diabetes. Butyrate, produced by the gut microbiota, has shown beneficial effects on glucose metabolism and may directly affect beta cell function, but the mechanisms are poorly described. The aim of this study was to investigate the effect of butyrate on IL-1β-induced β cell dysfunction. We showed that long-term exposure of mouse islets to non-cytotoxic concentrations of IL-1β impaired insulin secretion and content and reduced proliferation. This dysfunction was prevented when the islets were exposed to butyrate and butyrate alone also boosted insulin secretion. In contrast, butyrate further downregulated the proliferation. To get a better indication of mechanisms of actions we investigated the global mRNA expression profiles using RNA sequencing. Our results indicated that the protective effects of butyrate are associated with upregulation of secretion/transport-related genes and downregulation of inflammatory genes induced by IL-1β. In addition, several cell cycle related genes were strongly inhibited by butyrate. In conclusion, butyrate plays an essential role in supporting beta cell function under inflammatory conditions, suggesting a potential for therapeutic use in treatment and prevention of T2D.

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