Investigate the anti-tumor mechanisms of But4ManNAc and butyrate in two breast cancer cell lines
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE29922 | GEO | 2011/06/14
SECONDARY ACCESSION(S): PRJNA140723
REPOSITORIES: GEO
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Project description:But4ManNAc - an analog of ManNAc, the committed precursor of sialic acid - decreases metastatic potential, inhibits growth, and triggers apoptosis in many cancer cells. The anti-tumor effects of But4ManNAc may result from a synergistic interaction between butyrate-induced changes in gene expression and ManNAc-induced altered sialylation. This experiment provides insight into synergistic interactions by identifying changes in gene expression specific to But4ManNAc and not shared with butyrate. Specifically, microarrays will compare gene expression of metastatic breast cancer cells (MDA-MB-231) treated with But4ManNAc to that of cells treated with sodium butyrate at concentrations which inhibit invasiveness but do not trigger apoptosis. Differences in gene expression demonstrate a synergistic interaction between butyrate and sialylation as well as suggest mechanisms to account for this synergy. RNA preparations of treated and control metastatic breast cancer MDA-MB-231 cells were sent to Microarray Core (E). Five conditions where sent: cells treated with 50uM But4ManNAc, 125uM But4ManNAc, 50uM But5Man, 125uM But5Man, and Ethanol (control). Three replicate samples from each condition were used in the study. The RNA was amplified, labeled, and hybridized to the GLYCOv3 microarrays. Data was analyzed to identify differences in gene expression that demonstrate a synergistic interaction between butyrate and sialylation, as well as suggest mechanisms to account for this synergy.
2011-06-14 | E-GEOD-29922 | biostudies-arrayexpress
Project description:Chronic inflammatory bowel disease (IBD) causes disability, suffering and risk of colon cancer in over 30 million people globally. Here, we investigate 3 kindreds of IBD with mutations in the N-acetylgalactosamide alpha-2,6-sialyltransferase 1/ST6GALNAC1 (ST6) glycosyltransferase gene that is uniquely expressed in the goblet cells (GCs). These mutations cause defective sialic acid (SA) conjugation, elimination of the onco-antigen S-Tn (Sialyl-Tn), and altered glycosylation of the MUC2 protein, a key component of intestinal mucus. Decreased MUC2 sialylation increases susceptibility to bacterial proteolytic degradation and compromises the gastrointestinal (GI) mucus barrier. Mice harboring the patient ST6 mutations recapitulate human colitis and reveal that defective sialylation causes dysbiosis, butyrate overproduction, and impaired GI stem cell proliferation during injury. Thus, this new genetic disease illustrates how sialylation controls host-microbe homeostasis and reveals several new potential approaches to IBD treatment.
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Project description:Sialylation, the addition of negatively charged sialic acid sugars to terminal ends of glycans, is upregulated in most cancers. Hypersialylation supports multiple pro-tumor mechanisms such as enhanced migration and invasion, resistance to apoptosis and immune evasion. A current gap in knowledge is the lack of understanding on how the tumor microenvironment regulates cancer cell sialylation. The adipose niche is a main component of most peritoneal cancers’ microenvironment. This includes ovarian cancer (OC), which causes most deaths from all gynecologic cancers. In this report, we demonstrate that the adipose microenvironment is a critical regulator of OC cell sialylation.In vitroadipose conditioning led to an increase in both⍺2,3 and⍺2,6-linked cell surface sialic acids in both human and mouse models of OC.Adipose-induced sialylation reprogramming was also observedin vivofrom intra-peritoneal OC tumors seeded in the adipose-rich omentum. Mechanistically, we observed upregulation of at least three sialylatransferases, St3gal1, St6gal1 and St3galnac3.Hypersialylated OC cells consistently formed intra-peritoneal tumors in both immune-competent mice and immune-compromised athymic nude mice. In contrast, hyposiaylated OC cells persistently formed tumors only in athymic nude mice demonstrating that sialylation impacts OC tumor formation in an immune dependent manner. To our knowledge, this is the first demonstration of the effect of adipose microenvironment on OC tumor sialylation. Our results set the stage for translational applications targeting sialic acid pathways in OC and other peritoneal cancers.
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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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Project description:This SuperSeries is composed of the following subset Series: GSE15107: R1 mESC Exposed to Butyrate GSE15109: BG02 hESC Exposed to Butyrate GSE15110: H1 hESC Exposed to Butyrate Refer to individual Series
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