19 results found
Capece D, D'Andrea D, Begalli F, et al., 2021, Enhanced triacylglycerol catabolism by Carboxylesterase 1 promotes aggressive colorectal carcinoma., Journal of Clinical Investigation, ISSN: 0021-9738
The ability to adapt to low-nutrient microenvironments is essential for tumor-cell survival and progression in solid cancers, such as colorectal carcinoma (CRC). Signaling by the NF-κB transcription-factor pathway associates with advanced disease stages and shorter survival in CRC patients. NF-κB has been shown to drive tumor-promoting inflammation, cancer-cell survival and intestinal epithelial cell (IEC) dedifferentiation in mouse models of CRC. However, whether NF-κB affects the metabolic adaptations that fuel aggressive disease in CRC patients is unknown. Here, we identified carboxylesterase 1 (CES1) as an essential NF-κB-regulated lipase linking obesity-associated inflammation with fat metabolism and adaptation to energy stress in aggressive CRC. CES1 promoted CRC-cell survival via cell-autonomous mechanisms that fuel fatty-acid oxidation (FAO) and prevent the toxic build-up of triacylglycerols. We found that elevated CES1 expression correlated with worse outcomes in overweight CRC patients. Accordingly, NF-κB drove CES1 expression in CRC consensus molecular subtype (CMS)4, associated with obesity, stemness and inflammation. CES1 was also upregulated by gene amplifications of its transcriptional regulator, HNF4A, in CMS2 tumors, reinforcing its clinical relevance as a driver of CRC. This subtype-based distribution and unfavourable prognostic correlation distinguished CES1 from other intracellular triacylglycerol lipases and suggest CES1 could provide a route to treat aggressive CRC.
Chaudhari U, Ellis JK, Wagh V, et al., 2017, Metabolite signatures of doxorubicin induced toxicity in human induced pluripotent stem cell-derived cardiomyocytes., Amino Acids, Vol: 49, Pages: 1955-1963, ISSN: 0939-4451
Drug-induced off-target cardiotoxicity, particularly following anti-cancer therapy, is a major concern in new drug discovery and development. To ensure patient safety and efficient pharmaceutical drug development, there is an urgent need to develop more predictive cell model systems and distinct toxicity signatures. In this study, we applied our previously proposed repeated exposure toxicity methodology and performed (1)H NMR spectroscopy-based extracellular metabolic profiling in culture medium of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) exposed to doxorubicin (DOX), an anti-cancer agent. Single exposure to DOX did not show alteration in the basal level of extracellular metabolites while repeated exposure to DOX caused reduction in the utilization of pyruvate and acetate, and accumulation of formate compared to control culture medium. During drug washout, only pyruvate showed reversible effect and restored its utilization by hiPSC-CMs. On the other hand, formate and acetate showed irreversible effect in response to DOX exposure. DOX repeated exposure increased release of lactate dehydrogenase (LDH) in culture medium suggesting cytotoxicity events, while declined ATP levels in hiPSC-CMs. Our data suggests DOX perturbed mitochondrial metabolism in hiPSC-CMs. Pyruvate, acetate and formate can be used as metabolite signatures of DOX induced cardiotoxicity. Moreover, the hiPSC-CMs model system coupled with metabolomics technology offers a novel and powerful approach to strengthen cardiac safety assessment during new drug discovery and development.
Lau C-HE, Tredwell GD, Ellis JK, et al., 2017, Metabolomic characterisation of the effects of oncogenic PIK3CA transformation in a breast epithelial cell line, SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322
Somatic mutations in PIK3CA are frequently found in a number of human cancers, including breast cancer, altering cellular physiology and tumour sensitivity to chemotherapy. This renders PIK3CA an attractive molecular target for early detection and personalised therapy. Using 1H Nuclear Magnetic Resonance spectroscopy (NMR) and Gas Chromatography – Mass Spectrometery (GC-MS) together with 13C stable isotope-labelled glucose and glutamine as metabolic tracers, we probed the phenotypic changes in metabolism following a single copy knock-in of mutant PIK3CA (H1047R) in the MCF10A cell line, an important cell model for studying oncogenic transformation in breast tissues. We observed effects in several metabolic pathways, including a decrease in glycerophosphocholine level together with increases in glutaminolysis, de novo fatty acid synthesis and pyruvate entry into the tricarboxylic acid cycle. Our findings highlight altered glyceroplipid metabolism and lipogenesis, as key metabolic phenotypes of mutant PIK3CA transformation that are recapitulated in the MCF10A cellular model.
Keun H, Koufaris C, Ellis J, et al., 2015, Systematic integration of molecular profiles identifies miR-22 as a regulator of lipid and folate metabolism in breast cancer cells, Oncogene, Vol: 35, Pages: 2766-2776, ISSN: 1476-5594
Dysregulated microRNA (miRNA) mediate malignant phenotypes, including metabolic reprogramming. By performing an integrative analysis of miRNA and metabolome data for the NCI-60 cell line panel, we identified an miRNA cluster strongly associated with both c-Myc expression and global metabolic variation. Within this cluster the cancer-associated and cardioprotective miR-22 was shown to repress fatty acid synthesis and elongation in tumour cells by targeting ATP citrate lyase and fatty acid elongase 6, as well as impairing mitochondrial one-carbon metabolism by suppression of methylene tetrahydrofolate dehydrogenase/cyclohydrolase. Across several data sets, expression of these target genes were associated with poorer outcomes in breast cancer patients. Importantly, a beneficial effect of miR-22 on clinical outcomes in breast cancer was shown to depend on the expression levels of the identified target genes, demonstrating the relevance of miRNA/mRNA interactions to disease progression in vivo. Our systematic analysis establishes miR-22 as a novel regulator of tumour cell metabolism, a function that could contribute to the role of this miRNA in cellular differentiation and cancer development. Moreover, we provide a paradigmatic example of effect modification in outcome analysis as a consequence of miRNA-directed gene targeting, a phenomenon that could be exploited to improve patient prognosis and treatment.
Trousil S, Lee P, Pinato DJ, et al., 2014, Alterations of choline phospholipid metabolism in endometrial cancer are caused by choline kinase alpha overexpression and a hyperactivated deacylation pathway, Cancer Research, Vol: 74, Pages: 6867-6877, ISSN: 0008-5472
Metabolic rearrangements subsequent to malignant transformation are not well characterized in endometrial cancer. Identification of altered metabolites could facilitate imaging-guided diagnosis, treatment surveillance, and help to identify new therapeutic options. Here, we used high-resolution magic angle spinning magnetic resonance mass spectroscopy on endometrial cancer surgical specimens and normal endometrial tissue to investigate the key modulators that might explain metabolic changes, incorporating additional investigations using qRT-PCR, Western blotting, tissue microarrays (TMA), and uptake assays of [3H]-labeled choline. Lipid metabolism was severely dysregulated in endometrial cancer with various amino acids, inositols, nucleobases, and glutathione also altered. Among the most important lipid-related alterations were increased phosphocholine levels (increased 70% in endometrial cancer). Mechanistic investigations revealed that changes were not due to altered choline transporter expression, but rather due to increased expression of choline kinase α (CHKA) and an activated deacylation pathway, as indicated by upregulated expression of the catabolic enzymes LYPLA1, LYPLA2, and GPCPD1. We confirmed the significance of CHKA overexpression on a TMA, including a large series of endometrial hyperplasia, atypical hyperplasia, and adenocarcinoma tissues, supporting a role for CHKA in malignant transformation. Finally, we documented several-fold increases in the uptake of [3H]choline in endometrial cancer cell lines compared with normal endometrial stromal cells. Our results validate deregulated choline biochemistry as an important source of noninvasive imaging biomarkers for endometrial cancer. Cancer Res; 74(23); 6867–77. ©2014 AACR.
Blazquez M, Carretero A, Ellis JK, et al., 2013, A Combination of Transcriptomics and Metabolomics Uncovers Enhanced Bile Acid Biosynthesis in HepG2 Cells Expressing CCAAT/Enhancer-Binding Protein β (C/EBPβ), Hepatocyte Nuclear Factor 4α (HNF4α), and Constitutive Androstane Receptor (CAR), Journal of proteome research, Pages: 130515154744008-130515154744008
Vinken M, Maes M, Cavill R, et al., 2012, Proteomic and metabolomic responses to connexin43 silencing in primary hepatocyte cultures, Archives of Toxicology, Vol: 87, Pages: 883-894
Stewart JD, Marchan R, Lesjak MS, et al., 2012, Choline-releasing glycerophosphodiesterase EDI3 drives tumor cell migration and metastasis, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 109, Pages: 8155-8160, ISSN: 0027-8424
Ellis JK, Athersuch TJ, Thomas LD, et al., 2012, Metabolic profiling detects early effects of environmental and lifestyle exposure to cadmium in a human population., BMC medicine, Vol: 10, Pages: 61-61
Spurgeon DJ, Lawlor A, Hooper HL, et al., 2011, Outdoor and indoor cadmium distributions near an abandoned smelting works and their relations to human exposure, ENVIRONMENTAL POLLUTION, Vol: 159, Pages: 3425-3432, ISSN: 0269-7491
Cavill R, Kamburov A, Ellis JK, et al., 2011, Consensus-Phenotype Integration of Transcriptomic and Metabolomic Data Implies a Role for Metabolism in the Chemosensitivity of Tumour Cells, PLOS COMPUTATIONAL BIOLOGY, Vol: 7, ISSN: 1553-734X
Ellis JK, Athersuch TJ, Cavill R, et al., 2011, Metabolic response to low-level toxicant exposure in a novel renal tubule epithelial cell system, MOLECULAR BIOSYSTEMS, Vol: 7, Pages: 247-257, ISSN: 1742-206X
Keun HC, Ellis JK, Thomas LDK, et al., 2010, Metabolomics, human health and the environment: big opportunities for small molecule profiling, Publisher: OXFORD UNIV PRESS, Pages: 637-638, ISSN: 0267-8357
Ellis JK, Chan PH, Doktorova T, et al., 2010, Effect of the Histone Deacetylase Inhibitor Trichostatin A on the Metabolome of Cultured Primary Hepatocytes, JOURNAL OF PROTEOME RESEARCH, Vol: 9, Pages: 413-419, ISSN: 1535-3893
Ellis JK, 2008, Studies on the Molecular Basis of Methyl Eugenol Carcinogenicity
Methyl eugenol (ME) is a naturally occurring chemical found in many fruits and spices and is used as a flavour and fragrance in the food and cosmetic industries. ME has been shown to be a genotoxic hepatocarcinogen and form DNA adducts at high doses in rodents. It is possible that a previous two year NTP study in the rat over estimated the potential risk of methyl eugenol by administering the test material via a gavage dose regimen and at relatively high doses, which resulted in extensive gastric and hepatic toxicity.A low dose twenty eight day feeding study with F344 rats was undertaken at ME doses of 1, 5, 50 and 50 (gavage) mg/kg bw/day. This was intended to investigate the potential toxicity of ME at doses more representative of human exposure and via a dietary dose regimen. Tissue samples were macroscopically examined for signs of increased incidences of lesions, particularly the stomach and liver. Tissue samples were also assessed for hepatic proliferating cell nuclear antigen (PCNA) levels using a 96 well plate ELISA technique, pre- and post-study plasma gastrin levels using a competitive radio immuno-assay and hepatic ME-DNA adduct levels using nuclease P1 enhanced 32P-postlabelling. Potential hepatic transcriptional changes mediated by ME were also investigated in animals of the high dietary dose group (50 mg/kg bw/day) compared to dietary controls, using a differential gene display PCR assay.No overt signs of dose-related toxicity were observed in any of the treatment groups, when bodyweights, liver weights, histopathology, haematology, blood chemistry and urinalysis were examined. Analysis of the PCNA levels in the four dose groups showed no significant difference from the control values. Comparison of appropriate post-study vehicle control plasma gastrin concentrations to corresponding post-study dose group values also showed no significant differences in male and female rats. However, ME-DNA adducts were detected in hepatic DNA from both male and female
Ellis JK, Carmichael PL, Gooderham NJ, 2006, DNA adduct levels in the liver of the F344 rat treated with the natural flavour methyl eugenol, BTS and UKEMS Annual Meeting, Pages: 73-74
Ellis JK, Carmichael PL, Gooderham NJ, 2006, DNA adduct levels in the liver of the F344 rat treated with the natural flavour methyl eugenol, Joint Congress of the British-Toxicology-Society/29th Annual Meeting of the United-Kingdom-Environmental-Mutagen-Society, Publisher: ELSEVIER IRELAND LTD, Pages: 75-76, ISSN: 0300-483X
Ellis JK, Carmichael PL, Gooderham NJ, 2006, DNA adduct levels in the liver of the F344 rat treated with the natural flavour methyl eugenol, Publisher: OXFORD UNIV PRESS, Pages: 291-292, ISSN: 0267-8357
Ellis JK, Carmichael PL, Gooderham NJ, 2005, Toxicological Assessment of Low Dose Exposure to the Genotoxic Flavour Methyl Eugenol, International Conference on Environmental Mutagens (ICEMS2005)
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