Effect of Metformin on Biomarkers of Colorectal Tumor Cell Growth
Ontology highlight
ABSTRACT:
DISEASE(S): Colorectal Cancer,Colorectal Neoplasms
PROVIDER: 2127916 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
Similar Datasets
Project description:The biguanide drug metformin is a safe and widely prescribed drug for type 2 diabetes. Interestingly, hundreds of clinical trials were set to evaluate the potential role of metformin in the prevention and treatment of cancer including colorectal cancer (CRC). However, the metformin-induced cell signaling remains controversial. To interrogate cell signaling events and networks in CRC and explore the druggability of the metformin-rewired phosphorylation network, we performed a proteomic and phosphoproteomic analysis on a panel of 12 molecularly heterogeneous CRC cell lines. Using in-depth data-independent analysis mass spectrometry (DIA-MS), we profiled a total of 10,142 proteins and 56,080 phosphosites (P-sites) in CRC cells treated with metformin for 30 minutes and 24 hours. Our results indicate that metformin tends to not trigger or inhibit significant immediate phosphorylation events. Instead, it primarily remodels cell signaling in the long-term. Strikingly, the phosphorylation response to metformin was highly heterogeneous in the CRC panel. We further performed a network analysis to systematically estimate kinase/phosphatase activities and reconstruct signaling cascades in each cell line. We created a “MetScore” which catalogs the most consistently perturbed P-sites among CRC cells for future studies. Finally, we leveraged the metformin P-site signature to identify pharmacodynamic interactions, revealing and confirming a number of candidate metformin-interacting drugs, including navitoclax, a BCL-2/BCL-xL inhibitor. Together, we provide a state-of-the-art phosphoproteomic resource to explore the metformin-induced cell signaling for potential cancer therapeutics.
2023-02-18 | PXD036826 | Pride
Project description:Metformin is a drug used in the treatment of type 2 diabetes mellitus. Various studies have elucidated its anticancer properties. In this study, the effect of metformin on the differentiation and tumor microenvironment of colorectal cancer cells (CRC) was evaluated. For our study, we have used HCT116 colorectal cancer cell line and treated the cells with Metformin. Maximum tolerable non-toxic dose of metformin on HCT116 cells was determined by MTT assay. Cells were treated with 2.5 mM Metformin for 2 weeks. Analysis of apoptosis was done by flow cytometry using Annexin V / PI. CSC population was determined by flow cytometry using CSC markers CD44 and CD166. Metformin's ability to induce differentiation in CSC was assessed by analyzing Cytokeratin 20 (CK20) by flow cytometry and CDX1 (transcription factor for CK20), by RT-QPCR. Expression of Ki67 (proliferation marker) was done by RT-QPCR. RNA was isolated from 2.5 mM Metformin-treated and untreated cells populations. Microarray of untreated and 2.5 mM Metformin-treated RNA was done to study the whole genome transcriptomic changes.
2024-04-05 | GSE171478 | GEO
Project description:Metformin is the therapy of choice for treating type 2 diabetes and is currently repurposed for a wide range of diseases including aging. Recent evidence implicates the gut microbiota as a site of metformin action. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we performed C. elegans RNAseq to investigate the role of the metformin sensitive OP50 and metformin resistant OP50-MR E. coli microbiota in the drug effects on the host. Our data suggest an evolutionarily conserved bacterial mediation of metformin effects on host lipid metabolism and lifespan.
2019-07-13 | E-MTAB-7272 | biostudies-arrayexpress
Project description:The biguanide metformin has been shown to not only reduce circulating glucose levels but also suppress in vitro and in vivo growth of prostate cancer. However, the mechanisms underlying the anti-tumor effects of metformin in advanced prostate cancers are not fully understood. The goal of the present study was to define the signaling pathways regulated by metformin in androgen-receptor (AR) positive, castration-resistant prostate cancers. Our group used RNA sequencing (RNA-seq) to examine genes regulated by metformin within the C4-2 human prostate cancer cell line. Western blot analysis and quantitative RT-PCR were used to confirm alterations in gene expression and further explore regulation of protein expression by metformin. Data from the RNA-seq analysis revealed that metformin alters the expression of genes products involved in metabolic pathways, the spliceosome, RNA transport, and protein processing within the endoplasmic reticulum. Gene products involved in ErbB, insulin, mTOR, TGF-, MAPK, and Wnt signaling pathways are also regulated by metformin. A subset of metformin-regulated gene products were genes known to be direct transcriptional targets of p53 or AR. Together, our results suggest metformin regulates multiple pathways linked to tumor growth and progression within advanced prostate cancer cells.
2022-02-10 | GSE196343 | GEO
Project description:Objective: To investigate the effects of metformin on intestinal carbohydrate metabolism in vivo.
Method: Male mice preconditioned with a high-fat, high-sucrose diet were treated orally with metformin or a control solution for two weeks. Fructose metabolism, glucose production from fructose, and production of other fructose-derived metabolites were assessed using stably labeled fructose as a tracer.
Results: Metformin treatment decreased intestinal glucose levels and reduced incorporation of fructose-derived metabolites into glucose. This was associated with decreased intestinal fructose metabolism as indicated by decreased enterocyte F1P levels and diminished labeling of fructose-derived metabolites. Metformin also reduced fructose delivery to the liver. Proteomic analysis revealed that metformin coordinately down-regulated proteins involved carbohydrate metabolism including those involved in fructolysis and glucose production within intestinal tissue.
Conclusion: Metformin reduces intestinal fructose metabolism, and this is associated with broad-based changes in intestinal enzyme and protein levels involved in sugar metabolism indicating that metformin's effects on sugar metabolism are pleiotropic.
2024-04-27 | PXD041833 | JPOST Repository
Project description:Metformin, the most widely administered diabetes drug, has been proposed as a candidate for host directed therapy for tuberculosis although very little is known about its effects on human host responses to Mycobacterium tuberculosis. When added in vitro to PBMCs isolated from healthy non-diabetic volunteers, metformin increased glycolysis, inhibited the mTOR targets, strongly reduced M. tuberculosis induced production of TNF-alpha (-58%), IFN-gamma (-47%) and IL-beta (-20%), while increasing phagocytosis. In healthy subjects, in vivo metformin intake induced significant transcriptional changes in whole blood and isolated PBMCs, with substantial down-regulation of genes related to inflammation and the type 1 interferon response. Metformin intake also increased monocyte phagocytosis (by 1.5 to 2 fold) and ROS production (+20%). These results show that metformin in humans has a range of potentially beneficial effects on cellular metabolism, immune function and gene-transcriptional level, that affect innate host responses to M. tuberculosis. This underlines the importance of cellular metabolism for host immunity and supports a role for metformin as host-directed therapy for tuberculosis.
2019-06-16 | GSE102677 | GEO
Project description:Metformin is a medication that is commonly used in the treatment of diabetes. Recently small studies in cancer patients without diabetes suggest that metformin may benefit in lowering insulin levels. In those studies of patients with cancer but not diabetes, glucose (or sugar) levels in the blood are generally no lowered. Insulin and insulin-like growth factors affect the growth of cancer cells.
This randomized study will compare different interventions; exercise, exercise and metformin, metformin alone, or a control arm. The investigators are not directly testing how either exercise or metformin affects your disease. The investigators are testing how they affect insulin levels in your body as well as other blood markers. The investigators believe that these blood tests may either be related to cancer recurrences or be an early sign of cancer recurrences and they are testing how both exercise and metformin may change those markers.
| 2105645 | ecrin-mdr-crc
Project description:Metformin, the most widely administered diabetes drug, has been proposed as a candidate for host directed therapy for tuberculosis although very little is known about its effects on human host responses to Mycobacterium tuberculosis. When added in vitro to PBMCs isolated from healthy non-diabetic volunteers, metformin increased glycolysis, inhibited the mTOR targets, strongly reduced M. tuberculosis induced production of TNF-α (-58%), IFN-gamma (-47%) and IL-1β (-20%), while increasing phagocytosis. In healthy subjects, in vivo metformin intake induced significant transcriptional changes in whole blood and isolated PBMCs, with substantial down-regulation of genes related to inflammation and the type 1 interferon response. Metformin intake also increased monocyte phagocytosis (by 1.5 to 2 fold) and ROS production (+20%). These results show that metformin in humans has a range of potentially beneficial effects on cellular metabolism, immune function and gene-transcriptional level, that affect innate host responses to M. tuberculosis. This underlines the importance of cellular metabolism for host immunity and supports a role for metformin as host-directed therapy for tuberculosis.
2019-06-16 | GSE102633 | GEO
Project description:Optimal treatment for nonalcoholic steatohepatitis (NASH) has not yet been established, particularly for individuals without diabetes. We examined the effects of metformin, commonly used to treat patients with type 2 diabetes, on liver pathology in a non-diabetic NASH mouse model. Eight-week-old C57BL/6 mice were fed a methionine- and choline-deficient (MCD) + high fat (HF) diet with or without 0.1% metformin for 8 weeks.
2012-02-21 | E-GEOD-35961 | biostudies-arrayexpress
Project description:Reduced cancer incidence has been reported among type II diabetics treated with metformin. Metformin exhibits anti-proliferative and anti-neoplastic effects associated with inhibition of mTORC1, but the mechanisms are poorly understood. We provide the first genome-wide analysis of translational targets of canonical mTOR inhibitors (rapamycin and PP242) and metformin, revealing that metformin controls gene expression at the level of mRNA translation to an extent comparable to that of canonical mTOR inhibitors. Importantly, metformin's anti-proliferative activity can be explained by selective translational suppression of mRNAs encoding cell cycle regulators via the mTORC1/4E-BP pathway. Thus, metformin selectively inhibits mRNA translation of encoded proteins that promote neoplastic proliferation, motivating further studies of this compound and related biguanides in cancer prevention and treatment. MCF7 cells were treated with rapamycin, metformin or PP242 at concentrations that inhibited proliferation to 50% of control. Both cytoplasmic and polysome-associated mRNA was extracted from treatments and a vehicle treated control and probed with microarrays.
2012-05-20 | E-GEOD-36847 | biostudies-arrayexpress