L-norvaline affects the proliferation of breast cancer cells based on the microbiome and metabolome analysis

Abstract

Aims:The altered faecal metabolites and microbiota might be involved in the development of breast cancer. We aimed to investigate the effect of differential metabolites on the proliferative activity of breast cancer cells. Methods and Results:We collected faecal samples from 14 breast cancer patients and 14 healthy subjects. Untargeted metabolomics analysis, short-chain fatty acid (SCFA) targeted analysis, and 16S rDNA sequencing was performed. The gut metabolite composition of patients changed significantly. Levels of norvaline, glucuronate and galacturonate were lower in the cancer group than in the Control (p < 0.05).4-Methylcatechol and guaiacol increased (p < 0.05). Acetic acid and butyric acid were lower in the cancer group than in the control group (p < 0.05). Isobutyric acid and pentanoic acid were higher in the cancer group than in the control (p < 0.05). In the genus, the abundance of Rothia and Actinomyces increased in the cancer group, compared with the control group (p < 0.05). The differential microbiotas were clearly associated with differential metabolites but weakly with SCFAs. The abundance of Rothia and Actinomyces was markedly positively correlated with 4-methylcatechol and guaiacol (p < 0.05) and negatively correlated with norvaline (p < 0.05).L-norvaline inhibited the content of Arg-1 in a concentration-dependent manner.Compared with the L-norvaline or doxorubicin hydrochloride (DOX) group, the proliferation abilities of 4 T1 cells were the lowest in the L-norvaline combined with DOX (p < 0.05). The apoptosis rate increased (p < 0.05).Conclusions: Faecal metabolites and microbiota were significantly altered in breast cancer. Levels of differential metabolites (i.e. Norvaline) were significantly correlated with the abundance of differential microbiota. L-norvaline combined with DOX could clearly inhibit the proliferation activity of breast cancer cells.

Determination of short-chain fatty acids as putative biomarkers of cancer diseases by modern analytical strategies and tools: a review

“…( 61 ) gave opposite results as the study by Zhu et al. ( 60 ) in case of isobutyrate. The differences in the results may be caused by the type of samples used in the studies, i.e.…”

“…Zhu et al. ( 60 ), performed untargeted metabolomics, targeted metabolomics (SCFAs), and 16 S rDNA sequencing studies on fecal samples from 14 breast cancer patients and 14 healthy volunteers. The SCFAs content in fecal samples was analyzed quantitatively.…”

Metagenomics Analysis of Breast Microbiome Highlights the Abundance of Rothia Genus in Tumor Tissues

“…The LEfSe and the genus level heatmap analysis revealed higher abundance of Rothia genus in tumor tissues. A previous study showed that Rothia abundance in fecal samples of breast patients was negatively correlated with the level of the gut amino acid metabolite norvaline [ 35 ]. In the same study, they used L-norvaline, a type of norvaline, to investigate the inhibitory effect of L-norvaline on BC 4 T1 cells, as well as the relation between the L-norvaline concentration and the arginase1 level (Arg-1).…”

Identification of Bacterial Metabolites Modulating Breast Cancer Cell Proliferation and Epithelial-Mesenchymal Transition

“…However, yric acid plays multiple roles in breast cancer cells, including inhibitors of histone deacetylases (epigenetic modulators), metabolic substrates, and ligands of free fatty acid receptors (reviewed in [44]. However, yric acid levels decrease in the feces of breast cancer patients [41].…”