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High Levels of Prebiotic Resistant Starch in Diet Modulate Gene Expression and Metabolomic Profile in Pancreatic Cancer Xenograft Mice.

ABSTRACT: Cancer initiation and protection mainly derives from a systemic metabolic environment regulated by dietary patterns. Less is known about the impact of nutritional interventions in people with a diagnosis of cancer. The aim of our study was to investigate the effect of a diet rich in resistant starch (RS) on cell pathways modulation and metabolomic phenotype in pancreatic cancer xenograft mice. RNA-Seq experiments on tumor tissue showed that 25 genes resulted in dysregulated pancreatic cancer in mice fed with an RS diet, as compared to those fed with control diet. Moreover, in these two different mice groups, six serum metabolites were deregulated as detected by LC?MS analysis. A bioinformatic prediction analysis showed the involvement of the differentially expressed genes on insulin receptor signaling, circadian rhythm signaling, and cancer drug resistance among the three top canonical pathways, whilst cell death and survival, gene expression, and neurological disease were among the three top disease and biological functions. These findings shed light on the genomic and metabolic phenotype, contributing to the knowledge of the mechanisms through which RS may act as a potential supportive approach for enhancing the efficacy of existing cancer treatments.

SUBMITTER: Panebianco C

PROVIDER: S-EPMC6521226 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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High Levels of Prebiotic Resistant Starch in Diet Modulate Gene Expression and Metabolomic Profile in Pancreatic Cancer Xenograft Mice.

Panebianco Concetta C Villani Annacandida A Pazienza Valerio V

Nutrients 20190327 4

Cancer initiation and protection mainly derives from a systemic metabolic environment regulated by dietary patterns. Less is known about the impact of nutritional interventions in people with a diagnosis of cancer. The aim of our study was to investigate the effect of a diet rich in resistant starch (RS) on cell pathways modulation and metabolomic phenotype in pancreatic cancer xenograft mice. RNA-Seq experiments on tumor tissue showed that 25 genes resulted in dysregulated pancreatic cancer in ...[more]

PMID: 30934731

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Project description:Background/aimsPancreatic cancer (PC) is ranked as the fourth leading cause of cancer-related deaths worldwide. Despite recent advances in treatment options, a modest impact on the outcome of the disease is observed so far. We have previously demonstrated that short-term fasting cycles have the potential to improve the efficacy of chemotherapy against PC. The aim of this study was to assess the effect of an engineered resistant-starch (ERS) mimicking diet on the growth of cancer cell lines in vitro, on the composition of fecal microbiota, and on tumor growth in an in vivo pancreatic cancer mouse xenograft model.Materials and methodsBxPC-3, MIA PaCa-2 and PANC-1 cells were cultured in the control, and in the ERS-mimicking diet culturing condition, to evaluate tumor growth and proliferation pathways. Pancreatic cancer xenograft mice were subjected to an ERS diet to assess tumor volume and weight as compared to mice fed with a control diet. The composition and activity of fecal microbiota were further analyzed in growth experiments by isothermal microcalorimetry.ResultsPancreatic cancer cells cultured in an ERS diet-mimicking medium showed decreased levels of phospho-ERK1/2 (extracellular signal-regulated kinase proteins) and phospho-mTOR (mammalian target of rapamycin) levels, as compared to those cultured in standard medium. Consistently, xenograft pancreatic cancer mice subjected to an ERS diet displayed significant retardation in tumor growth. In in vitro growth experiments, the fecal microbial cultures from mice fed with an ERS diet showed enhanced growth on residual substrates, higher production of formate and lactate, and decreased amounts of propionate, compared to fecal microbiota from mice fed with the control diet.ConclusionA positive effect of the ERS diet on composition and metabolism of mouse fecal microbiota shown in vitro is associated with the decrease of tumor progression in the in vivo PC xenograft mouse model. These results suggest that engineered dietary interventions could be supportive as a synergistic approach to enhance the efficacy of existing cancer treatments in pancreatic cancer patients.

Project description:The influence of bovine diet on the metabolome of reconstituted skim milk powder (SMP) and protein ingredients produced from the milk of cows fed on pasture or concentrate-based diets was investigated. Cows were randomly assigned to diets consisting of perennial ryegrass only (GRS), perennial ryegrass/white clover sward (CLV), or indoor total mixed ration (TMR) for an entire lactation. Raw milk obtained from each group was processed at pilot scale, to produce SMP and sweet whey, and SMP was further processed at laboratory scale, to yield ideal whey and acid whey. The total amino acid composition and metabolome of each sample were analyzed, using high-performance cation exchange and a targeted combination of direct-injection mass spectrometry and reverse-phase liquid chromatography-tandem mass spectrometry (LC-MS/MS), respectively. The nitrogen composition of the products from each of the diets was similar, with one exception being the significantly higher nonprotein nitrogen content in TMR-derived skim milk powder than that from the GRS system. Total amino acid analysis showed significantly higher concentrations of glycine in GRS- and CLV-derived sweet whey and acid whey than in those from TMR. The cysteine contents of CLV-derived ideal whey and acid whey were significantly higher than for TMR, while the valine content of GRS-derived acid whey was significantly higher than TMR. The phenylalanine content of GRS-derived ideal whey was significantly higher than that from CLV. Metabolomic analysis showed significantly higher concentrations of the metabolites glutamine, valine, and phosphocreatine in each ingredient type derived from TMR than those from GRS or CLV, while the serine content of each GRS-derived ingredient type was significantly higher than that in TMR-derived ingredients. These results demonstrate that the type of bovine feeding system used can have a significant effect on the amino acid composition and metabolome of skim milk and whey powders and may aid in the selection of raw materials for product manufacture, while the clear separation between the samples gives further evidence for distinguishing milk products produced from different feeding systems based on LC-MS/MS.

Dataset Information

High Levels of Prebiotic Resistant Starch in Diet Modulate Gene Expression and Metabolomic Profile in Pancreatic Cancer Xenograft Mice.

Publications

High Levels of Prebiotic Resistant Starch in Diet Modulate Gene Expression and Metabolomic Profile in Pancreatic Cancer Xenograft Mice.

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