关键词： 1H–13C HMBC, 1H–13C Heteronuclear Multiple Bond Correlation Spectroscopy 1H–13C HSQC, 1H–13C Heteronuclear Single Quantum Coherence Spectroscopy 1H–1H COSY, 1H–1H Correlation Spectroscopy 1H–1H TOCSY, 1H–1H Total Correlation Spectroscopy ADP, Adenosine diphosphate AMP, Adenosine monophosphate ATP, Adenosine triphosphate Ace, Acetate Ach, Acetylcholine Ala, Alanine CRC, Colorectal Cancer Caco-2, Human Colon Adenocarcinoma Cho, Choline CoA, Coenzyme A Cre, Creatine DCFH-DA, Dichloro-Dihydro-Fluorescein Diacetate DEGs, Differentially Expressed Genes DMEM, Dulbecco's Modified Eagle Medium DMG, Dimethylglycine DNA, Deoxyribonucleic Acid EP, Eppendorf FA, Formate FDR, False Discovery Rate Fru, Fructose Fum, Fumaric acid GLS, Glutaminase GSEA, Gene Set Enrichment Analysis GSH, Glutathione Gal-1-P, Galactose-1-phosphate Glc, Glucose Gln, Glutamine Glu, Glutamate Gly, Glycine HCT116, Human Colorectal Carcinoma Cell Line HEK, Human Embryonic Kidney cells HT29, Human Colorectal Adenocarcinoma Cell Line with Epithelial Morphology His, Histidine Ile, Isoleucine J-Res, J-resolved Spectroscopy LDH, Lactate Dehydrogenase Lac, Lactate Leu, Leucine Lys, Lysine MCF-7, Human Breast Cancer Cell Line with Estrogen MCT, Monocarboxylate Transporters Met, Methionine MetS, Metabolic Syndrome Mitochondrial function NAD+, Nicotinamide adenine dinucleotide NAG, N-Acetyl-L-Glutamine NMR, Nuclear Magnetic Resonance NMR-based Metabolomics NOESY, Nuclear Overhauser Effect Spectroscopy O-PLS-DA, Orthogonal Projection to the Latent Structures Discriminant Analysis PA, Pantothenate PC, Phosphocholine PCA, Principal Component Analysis PDC, Pyruvate Decarboxylase PDK, Pyruvate Dehydrogenase Kinase PKC, Protein Kinase C PPP, Pentose Phosphate Pathway Phe, Phenylalanine Pyr, Pyruvate RNA, Ribonucleic Acid ROS, Reactive Oxygen Species RPKM, Reads per Kilobase of Transcript per Million Reads Mapped Reactive oxygen species SCFAs, Short Chain Fatty Acids SLC, Solute-Carrier Genes Short-chain fatty acids Suc, Succinate T2DM, Type 2 Diabetes TCA, Tricarboxylic Acid Tau, Taurine Thr, Threonine Transcriptomics Tyr, Tyrosine UDP, Uridine 5′-diphosphate UDP-GLC, UDP Glucose UDPG, UDP Glucuronate UDPGs, UDP Glucose and UDP Glucuronate UMP, Uridine 5′-monophosphate Val, Valine WST-1, Water-Soluble Tetrazolium salts dDNP, dissolution Dynamic Nuclear Polarization qRT-PCR, Real-Time Quantitative Reverse Transcription Polymerase Chain Reaction α-KIV, α-Keto-isovalerate α-KMV, α-keto-β-methyl-valerate

来  源：   DOI：10.1016/j.csbj.2023.02.022   PDF(Pubmed)

Abstract：
Short-chain fatty acids (SCFAs) exhibit anticancer activity in cellular and animal models of colon cancer. Acetate, propionate, and butyrate are the three major SCFAs produced from dietary fiber by gut microbiota fermentation and have beneficial effects on human health. Most previous studies on the antitumor mechanisms of SCFAs have focused on specific metabolites or genes involved in antitumor pathways, such as reactive oxygen species (ROS) biosynthesis. In this study, we performed a systematic and unbiased analysis of the effects of acetate, propionate, and butyrate on ROS levels and metabolic and transcriptomic signatures at physiological concentrations in human colorectal adenocarcinoma cells. We observed significantly elevated levels of ROS in the treated cells. Furthermore, significantly regulated signatures were involved in overlapping pathways at metabolic and transcriptomic levels, including ROS response and metabolism, fatty acid transport and metabolism, glucose response and metabolism, mitochondrial transport and respiratory chain complex, one-carbon metabolism, amino acid transport and metabolism, and glutaminolysis, which are directly or indirectly linked to ROS production. Additionally, metabolic and transcriptomic regulation occurred in a SCFAs types-dependent manner, with an increasing degree from acetate to propionate and then to butyrate. This study provides a comprehensive analysis of how SCFAs induce ROS production and modulate metabolic and transcriptomic levels in colon cancer cells, which is vital for understanding the mechanisms of the effects of SCFAs on antitumor activity in colon cancer.
摘要：
短链脂肪酸（SCFA）在结肠癌的细胞和动物模型中表现出抗癌活性。醋酸盐,丙酸盐,和丁酸盐是由膳食纤维通过肠道微生物群发酵产生的三种主要SCFA，对人体健康具有有益作用。以往对SCFA抗肿瘤机制的研究大多集中在参与抗肿瘤通路的特定代谢产物或基因上,如活性氧（ROS）生物合成。在这项研究中,我们对乙酸盐的影响进行了系统和无偏见的分析，丙酸盐,和丁酸盐对人结肠直肠腺癌细胞生理浓度下ROS水平以及代谢和转录组特征的影响。我们观察到在处理的细胞中ROS水平显著升高。此外，显著调节的信号涉及代谢和转录组水平的重叠途径，包括ROS反应和代谢，脂肪酸运输和代谢，葡萄糖反应和代谢，线粒体运输和呼吸链复合物，一碳代谢，氨基酸运输和代谢，和谷氨酰胺分解，它们与ROS的产生直接或间接相关。此外,代谢和转录组调节以SCFAs类型依赖的方式发生，从乙酸到丙酸再到丁酸的程度逐渐增加。本研究全面分析了SCFA如何诱导ROS产生并调节结肠癌细胞的代谢和转录水平。这对于理解SCFA对结肠癌抗肿瘤活性的作用机制至关重要。
公众号