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Cancer & Metabolism

Loreta M Rodrigues, Santiago Uribe-Lewis, Basetti Madhu, Davina J Honess, Marion Stubbs, John R Griffiths
BACKGROUND: Ketone bodies have both metabolic and epigenetic roles in cancer. In several studies, they showed an anti-cancer effect via inhibition of histone deacetylases; however, other studies observed faster tumour growth. The related molecule butyrate also inhibits growth of some cancer cells and accelerates it in others. This "butyrate paradox" is thought to be due to butyrate mediating histone acetylation and thus inhibiting cell proliferation in cancers that preferentially utilise glucose (the Warburg effect); whereas in cells that oxidise butyrate as a fuel, it fails to reach inhibitory concentrations and can stimulate growth...
2017: Cancer & Metabolism
Renaud Vatrinet, Giulia Leone, Monica De Luise, Giulia Girolimetti, Michele Vidone, Giuseppe Gasparre, Anna Maria Porcelli
Deregulated metabolism is a well-established hallmark of cancer. At the hub of various metabolic pathways deeply integrated within mitochondrial functions, the α-ketoglutarate dehydrogenase complex represents a major modulator of electron transport chain activity and tricarboxylic acid cycle (TCA) flux, and is a pivotal enzyme in the metabolic reprogramming following a cancer cell's change in bioenergetic requirements. By contributing to the control of α-ketoglutarate levels, dynamics, and oxidation state, the α-ketoglutarate dehydrogenase is also essential in modulating the epigenetic landscape of cancer cells...
2017: Cancer & Metabolism
Rae-Anne Hardie, Ellen van Dam, Mark Cowley, Ting-Li Han, Seher Balaban, Marina Pajic, Mark Pinese, Mary Iconomou, Robert F Shearer, Jessie McKenna, David Miller, Nicola Waddell, John V Pearson, Sean M Grimmond, Leonid Sazanov, Andrew V Biankin, Silas Villas-Boas, Andrew J Hoy, Nigel Turner, Darren N Saunders
BACKGROUND: Pancreatic cancer has a five-year survival rate of ~8%, with characteristic molecular heterogeneity and restricted treatment options. Targeting metabolism has emerged as a potentially effective therapeutic strategy for cancers such as pancreatic cancer, which are driven by genetic alterations that are not tractable drug targets. Although somatic mitochondrial genome (mtDNA) mutations have been observed in various tumors types, understanding of metabolic genotype-phenotype relationships is limited...
2017: Cancer & Metabolism
Seher Balaban, Robert F Shearer, Lisa S Lee, Michelle van Geldermalsen, Mark Schreuder, Harrison C Shtein, Rose Cairns, Kristen C Thomas, Daniel J Fazakerley, Thomas Grewal, Jeff Holst, Darren N Saunders, Andrew J Hoy
BACKGROUND: Obesity is associated with increased recurrence and reduced survival of breast cancer. Adipocytes constitute a significant component of breast tissue, yet their role in provisioning metabolic substrates to support breast cancer progression is poorly understood. RESULTS: Here, we show that co-culture of breast cancer cells with adipocytes revealed cancer cell-stimulated depletion of adipocyte triacylglycerol. Adipocyte-derived free fatty acids were transferred to breast cancer cells, driving fatty acid metabolism via increased CPT1A and electron transport chain complex protein levels, resulting in increased proliferation and migration...
2017: Cancer & Metabolism
Rachel S Kelly, Jennifer A Sinnott, Jennifer R Rider, Ericka M Ebot, Travis Gerke, Michaela Bowden, Andreas Pettersson, Massimo Loda, Howard D Sesso, Philip W Kantoff, Neil E Martin, Edward L Giovannucci, Svitlana Tyekucheva, Matthew Vander Heiden, Lorelei A Mucci
BACKGROUND: Understanding the biologic mechanisms underlying the development of lethal prostate cancer is critical for improved therapeutic and prevention strategies. In this study we explored the role of tumor metabolism in prostate cancer progression using mRNA expression profiling of seven metabolic pathways; fatty acid metabolism, glycolysis/gluconeogenesis, oxidative phosphorylation, pentose phosphate, purine metabolism, pyrimidine metabolism and the tricarboxylic acid cycle. METHODS: The study included 404 men with archival formalin-fixed, paraffin-embedded prostate tumor tissue from the prospective Health Professionals Follow-up Study and Physicians' Health Study...
2016: Cancer & Metabolism
Parmanand Malvi, Balkrishna Chaube, Shivendra Vikram Singh, Naoshad Mohammad, Vimal Pandey, Maleppillil Vavachan Vijayakumar, Revathy Meenatheril Radhakrishnan, Muralidharan Vanuopadath, Sudarslal Sadasivan Nair, Bipin Gopalakrishnan Nair, Manoj Kumar Bhat
BACKGROUND: Obesity-related cellular, metabolic, and molecular alterations have been shown to increase cancer risk and tumor progression and are associated with poorer therapeutic outcome in cancer patients. However, the impact of obesity and weight-control interventions on the therapeutic response in melanoma is poorly understood. METHODS: High fat diet (HFD)-induced obese mouse model was used in this study to evaluate the outcome of dacarbazine (DTIC) therapy in melanoma...
2016: Cancer & Metabolism
Menghan Liu, Lake-Ee Quek, Ghazal Sultani, Nigel Turner
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a common malignancy with dismal prognosis. Metastatic spread and therapeutic resistance, the main causes of PDAC-related mortalities, are both partially underlined by the epithelial-mesenchymal transition (EMT) of PDAC cells. While the role of Warburg metabolism has been recognized in supporting rapid cellular growth and proliferation in many cancer types, less is known about the metabolic changes occurring during EMT, particularly in the context of PDAC...
2016: Cancer & Metabolism
Stephanie Sprowl-Tanio, Amber N Habowski, Kira T Pate, Miriam M McQuade, Kehui Wang, Robert A Edwards, Felix Grun, Yung Lyou, Marian L Waterman
BACKGROUND: There is increasing evidence that oncogenic Wnt signaling directs metabolic reprogramming of cancer cells to favor aerobic glycolysis or Warburg metabolism. In colon cancer, this reprogramming is due to direct regulation of pyruvate dehydrogenase kinase 1 (PDK1) gene transcription. Additional metabolism genes are sensitive to Wnt signaling and exhibit correlative expression with PDK1. Whether these genes are also regulated at the transcriptional level, and therefore a part of a core metabolic gene program targeted by oncogenic WNT signaling, is not known...
2016: Cancer & Metabolism
Laura M Lashinger, Ciara H O'Flanagan, Sarah M Dunlap, Audrey J Rasmussen, Shannon Sweeney, Jessie Yangxiang Guo, Alessia Lodi, Stefano Tiziani, Eileen White, Stephen D Hursting
BACKGROUND: Calorie restriction (CR) prevents obesity and exerts anticancer effects in many preclinical models. CR is also increasingly being used in cancer patients as a sensitizing strategy prior to chemotherapy regimens. While the beneficial effects of CR are widely accepted, the mechanisms through which CR affects tumor growth are incompletely understood. In many cell types, CR and other nutrient stressors can induce autophagy, which provides energy and metabolic substrates critical for cancer cell survival...
2016: Cancer & Metabolism
Sergey Tumanov, Vinay Bulusu, Eyal Gottlieb, Jurre J Kamphorst
BACKGROUND: Acetyl-CoA is a key metabolic intermediate with roles in the production of energy and biomass, as well as in metabolic regulation. It was recently found that acetate is crucial for maintaining acetyl-CoA production in hypoxic cancer cells. However, the availability of free acetate in the tumor environment and how much tumor cells consume remains unknown. Similarly, much is still to be learned about changes in the dynamics and distribution of acetylation in response to tumor-relevant conditions...
2016: Cancer & Metabolism
Mark A Keibler, Thomas M Wasylenko, Joanne K Kelleher, Othon Iliopoulos, Matthew G Vander Heiden, Gregory Stephanopoulos
BACKGROUND: The study of cancer metabolism has been largely dedicated to exploring the hypothesis that oncogenic transformation rewires cellular metabolism to sustain elevated rates of growth and division. Intense examination of tumors and cancer cell lines has confirmed that many cancer-associated metabolic phenotypes allow robust growth and survival; however, little attention has been given to explicitly identifying the biochemical requirements for cell proliferation in a rigorous manner in the context of cancer metabolism...
2016: Cancer & Metabolism
Michelle A C Reed, Christian Ludwig, Christopher M Bunce, Farhat L Khanim, Ulrich L Günther
BACKGROUND: The role of anaplerotic nutrient entry into the Krebs cycle via pyruvate carboxylase has been the subject of increased scrutiny and in particular whether this is dysregulated in cancer. Here, we use a tracer-based NMR analysis involving high-resolution (1)H-(13)C-HSQC spectra to assess site-specific label incorporation into a range of metabolite pools, including malate, aspartate and glutamate in the acute myeloid leukaemia cell line K562. We also determine how this is affected following treatment with the redeployed drug combination of the lipid-regulating drug bezafibrate and medroxyprogesterone (BaP)...
2016: Cancer & Metabolism
Johannes C van der Mijn, David J Panka, Andrew K Geissler, Henk M Verheul, James W Mier
Molecular profiling studies of tumor tissue from patients with clear cell renal cell cancer (ccRCC) have revealed extensive metabolic reprogramming in this disease. Associations were found between metabolic reprogramming, histopathologic Fuhrman grade, and overall survival of patients. Large-scale genomics, proteomics, and metabolomic analyses have been performed to identify the molecular players in this process. Genes involved in glycolysis, the pentose phosphate pathway, glutamine metabolism, and lipogenesis were found to be upregulated in renal cell cancer (RCC) specimens as compared to normal tissue...
2016: Cancer & Metabolism
Lake-Ee Quek, Menghan Liu, Sanket Joshi, Nigel Turner
BACKGROUND: Glucose and glutamine are the two dominant metabolic substrates in cancer cells. In (13)C tracer experiments, however, it is necessary to account for all significant input substrates, as some natural (unlabelled) substrate in the medium, often derived from serum, can be metabolised by cells despite not showing signs of net consumption. RESULTS: Using [U-(13)C6]-glucose tracers and measuring extracellular metabolite enrichments by GC-MS, we found that pancreatic cells HPDE and PANC-1 secrete lactate, pyruvate, TCA cycle metabolites and non-essential amino acids synthesised from glucose...
2016: Cancer & Metabolism
Tonje H Haukaas, Leslie R Euceda, Guro F Giskeødegård, Santosh Lamichhane, Marit Krohn, Sandra Jernström, Miriam R Aure, Ole C Lingjærde, Ellen Schlichting, Øystein Garred, Eldri U Due, Gordon B Mills, Kristine K Sahlberg, Anne-Lise Børresen-Dale, Tone F Bathen
BACKGROUND: The heterogeneous biology of breast cancer leads to high diversity in prognosis and response to treatment, even for patients with similar clinical diagnosis, histology, and stage of disease. Identifying mechanisms contributing to this heterogeneity may reveal new cancer targets or clinically relevant subgroups for treatment stratification. In this study, we have merged metabolite, protein, and gene expression data from breast cancer patients to examine the heterogeneity at a molecular level...
2016: Cancer & Metabolism
Dustin G Brown, Sangeeta Rao, Tiffany L Weir, Joanne O'Malia, Marlon Bazan, Regina J Brown, Elizabeth P Ryan
BACKGROUND: Colorectal cancers (CRC) are associated with perturbations in cellular amino acids, nucleotides, pentose-phosphate pathway carbohydrates, and glycolytic, gluconeogenic, and tricarboxylic acid intermediates. A non-targeted global metabolome approach was utilized for exploring human CRC, adjacent mucosa, and stool. In this pilot study, we identified metabolite profile differences between CRC and adjacent mucosa from patients undergoing colonic resection. Metabolic pathway analyses further revealed relationships between complex networks of metabolites...
2016: Cancer & Metabolism
Ilinca Georgescu, Robert J Gooding, R Christopher Doiron, Andrew Day, Shamini Selvarajah, Chris Davidson, David M Berman, Paul C Park
BACKGROUND: Gleason scores (GS) 3+3 and 3+4 prostate cancers (PCa) differ greatly in their clinical courses, with Gleason pattern (GP) 4 representing a major independent risk factor for cancer progression. However, Gleason grade is not reliably ascertained by diagnostic biopsy, largely due to sampling inadequacies, subjectivity in the Gleason grading procedure, and a lack of more objective biomarker assays to stratify prostate cancer aggressiveness. In most aggressive cancer types, the tumor microenvironment exhibits a reciprocal pro-tumorigenic metabolic phenotype consistent with the reverse Warburg effect (RWE)...
2016: Cancer & Metabolism
Stacey L Borrego, Johannes Fahrmann, Rupsa Datta, Chiara Stringari, Dmitry Grapov, Michael Zeller, Yumay Chen, Ping Wang, Pierre Baldi, Enrico Gratton, Oliver Fiehn, Peter Kaiser
BACKGROUND: The majority of cancer cells have a unique metabolic requirement for methionine that is not observed in normal, non-tumorigenic cells. This phenotype is described as "methionine dependence" or "methionine stress sensitivity" in which cancer cells are unable to proliferate when methionine has been replaced with its metabolic precursor, homocysteine, in cell culture growth media. We focus on the metabolic response to methionine stress in the triple negative breast cancer cell line MDA-MB-468 and its methionine insensitive derivative cell line MDA-MB-468res-R8...
2016: Cancer & Metabolism
Daniel Weindl, Thekla Cordes, Nadia Battello, Sean C Sapcariu, Xiangyi Dong, Andre Wegner, Karsten Hiller
BACKGROUND: Metabolism gained increasing interest for the understanding of diseases and to pinpoint therapeutic intervention points. However, classical metabolomics techniques only provide a very static view on metabolism. Metabolic flux analysis methods, on the other hand, are highly targeted and require detailed knowledge on metabolism beforehand. RESULTS: We present a novel workflow to analyze non-targeted metabolome-wide stable isotope labeling data to detect metabolic flux changes in a non-targeted manner...
2016: Cancer & Metabolism
Behjatolah Monzavi-Karbassi, Rhonda Gentry, Varinder Kaur, Eric R Siegel, Fariba Jousheghany, Srikanth Medarametla, Barbara J Fuhrman, A Mazin Safar, Laura F Hutchins, Thomas Kieber-Emmons
BACKGROUND: The effect of moderately elevated blood glucose levels among non-diabetic subjects on cancer prognosis is not well described. The goal of this study was to examine the association of elevated random blood glucose (RBG) levels in non-diabetic breast cancer patients with overall survival (OS) and time to tumor recurrence (TTR). RESULTS: Forty-nine deaths and 32 recurrences occurred among 148 eligible study subjects during 855.44 person-years of follow-up, with median follow-up of 5...
2016: Cancer & Metabolism
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