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Cancer AND glutamine

Fariba Tayyari, G A Nagana Gowda, Olufunmilayo F Olopade, Richard Berg, Howard H Yang, Maxwell P Lee, Wilfred F Ngwa, Suresh K Mittal, Daniel Raftery, Sulma I Mohammed
Breast cancer, a heterogeneous disease with variable pathophysiology and biology, is classified into four major subtypes. While hormonal- and antibody-targeted therapies are effective in the patients with luminal and HER-2 subtypes, the patients with triple-negative breast cancer (TNBC) subtype do not benefit from these therapies. The incidence rates of TNBC subtype are higher in African-American women, and the evidence indicates that these women have worse prognosis compared to women of European descent. The reasons for this disparity remain unclear but are often attributed to TNBC biology...
February 20, 2018: Oncotarget
Natthakan Thongon, Chiara Zucal, Vito Giuseppe D'Agostino, Toma Tebaldi, Silvia Ravera, Federica Zamporlini, Francesco Piacente, Ruxanda Moschoi, Nadia Raffaelli, Alessandro Quattrone, Alessio Nencioni, Jean-Francois Peyron, Alessandro Provenzani
Background: Inhibitors of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD+ biosynthesis from nicotinamide, exhibit anticancer effects in preclinical models. However, continuous exposure to NAMPT inhibitors, such as FK866, can induce acquired resistance. Methods: We developed FK866-resistant CCRF-CEM (T cell acute lymphoblastic leukemia) and MDA MB231 (breast cancer) models, and by exploiting an integrated approach based on genetic, biochemical, and genome wide analyses, we annotated the drug resistance mechanisms...
2018: Cancer & Metabolism
Balraj Singh, Vanessa N Sarli, Laura J Washburn, Milan R Raythatha, Anthony Lucci
We previously described a strategy for selecting highly adaptable rare triple-negative breast cancer (TNBC) cells based on their ability to survive a severe and prolonged metabolic challenge, e.g., a lack of glutamine. We hypothesized that metabolically adaptable (MA) cancer cells selected from the SUM149 cell line in this manner have the capacity to survive a variety of challenges that postulated "decathlon winner" cancer cells must survive to succeed in metastasis. These MA cells were resistant to glutaminase inhibitor CB-839, as predicted from their ability to proliferate without exogenous glutamine...
February 16, 2018: Oncotarget
Li Wang, Jing-Jing Li, Li-Yu Guo, Peipei Li, Zhiqiang Zhao, Haisheng Zhou, Li-Jun Di
Glucose and Glutamine are two essential ingredients for cell growth. However, it remains open for investigation whether there is a general mechanism that coordinates the consumption of glucose and glutamine in cancer cells. Glutamine is mainly metabolized through the glutaminolysis pathway and our previous report indicated that CtBP increases GDH activity and promotes glutaminolysis through repressing the expression of SIRT4, a well-known mitochondrion-located factor that inhibits glutaminolysis pathway. CtBP is known to be a sensor of intracellular metabolic status; we thus hypothesized that a consensus CtBP-SIRT4-GDH axis may mediate the crosstalk between glycolysis and glutaminolysis...
March 13, 2018: Oncogenesis
Jian-Ming Hu, Huang-Tao Sun
BACKGROUND: To find potential serum biomarkers of microwave ablation (MWA) for treatment of human lung cancer by1 H nuclear magnetic resonance (NMR)-based metabolomics analysis. METHODS: Serum specimens collected from 43 healthy individuals, 39 patients with advanced non-small cell lung cancer (NSCLC) and 38 NSCLC patients treated with MWA, were subjected to1 H NMR-based metabolomics analysis. Partial least squares discriminant analysis was used to analyze the data...
March 12, 2018: Radiation Oncology
Tianyu Han, Weihua Zhan, Mingxi Gan, Fanrong Liu, Bentong Yu, Y Eugene Chin, Jian-Bin Wang
Glutamine metabolism plays an important role in cancer development and progression. Glutaminase C (GAC), the first enzyme in glutaminolysis, has emerged as an important target for cancer therapy and many studies have focused on the mechanism of enhanced GAC expression in cancer cells. However, little is known about the post-translational modification of GAC. Here, we report that phosphorylation is a crucial post-translational modification of GAC, which is responsible for the higher glutaminase activity in lung tumor tissues and cancer cells...
March 7, 2018: Cell Research
Maria E Mycielska, Katja Dettmer-Wilde, Petra Rümmele, Katharina M Schmidt, Cornelia Prehn, Vladimir Milenkovic, Wolfgang Jagla, M Gregor Madej, Margareta Lantow, Moritz T Schladt, Alexander Cecil, Gudrun E Koehl, Elke Eggenhofer, Christian Wachsmuth, Vadivel Ganapathy, Hans J Schlitt, Karl Kunzelmann, Christine Ziegler, Christian H Wetzel, Andreas Gaumann, Sven A Lang, Jerzy Adamski, Peter J Oefner, Edward K Geissler
Glycolysis and fatty acid synthesis are highly active in cancer cells through cytosolic citrate metabolism, with intracellular citrate primarily derived from either glucose or glutamine via the tricarboxylic acid cycle. We show here that extracellular citrate is supplied to cancer cells through a plasma membrane-specific variant of the mitochondrial citrate transporter (pmCiC). Metabolomic analysis revealed that citrate uptake broadly affected cancer cell metabolism through citrate-dependent metabolic pathways...
March 6, 2018: Cancer Research
Jalal K Siddiqui, Elizabeth Baskin, Mingrui Liu, Carmen Z Cantemir-Stone, Bofei Zhang, Russell Bonneville, Joseph P McElroy, Kevin R Coombes, Ewy A Mathé
BACKGROUND: Integration of transcriptomic and metabolomic data improves functional interpretation of disease-related metabolomic phenotypes, and facilitates discovery of putative metabolite biomarkers and gene targets. For this reason, these data are increasingly collected in large (> 100 participants) cohorts, thereby driving a need for the development of user-friendly and open-source methods/tools for their integration. Of note, clinical/translational studies typically provide snapshot (e...
March 5, 2018: BMC Bioinformatics
Y B Lou, F X Fan, Y C Mu, X Dong
The aim of this study was to analyze metabolite differences in pancreatic cancer and diabetic patients, to better diagnose these diseases. Gas chromatography-mass spectrometry was used to evaluate the metabolomic differences in blood samples of 50 pancreatic patients, 50 diabetic patients and 50 healthy people. Metabonomic data was analyzed with primary component analysis and discriminant analysis. The results show that pancreatic cancer patients, diabetic patients and healthy people can have significantly distinct metabolite profiles...
January 2018: Journal of Biological Regulators and Homeostatic Agents
Zongdong Li, Natasha M Nesbitt, Lisa E Malone, Dimitri V Gnatenko, Song Wu, Daifeng Wang, Wei Zhu, Geoffrey D Girnun, Wadie F Bahou
Bioenergetic requirements of hematopoietic stem cells (HSC) and pluripotent stem cells (PSC) vary with lineage fate, and cellular adaptations rely largely on substrate (glucose/glutamine) availability and mitochondrial function to balance TCA-derived anabolic and redox-regulated antioxidant functions.  Heme synthesis and degradation converge in a linear pathway that utilizes TCA cycle-derived carbon in cataplerotic reactions of tetrapyrrole biosynthesis, terminated by NAD(P)H-dependent biliverdin reductases (IXα, BLVRA and IXβ, BLVRB) that lead to bilirubin generation and cellular antioxidant functions...
March 2, 2018: Biochemical Journal
Tamer M Sakr, Mohammed A Khedr, Hassan M Rashed, Maged E Mohamed
l-Phosphinothricin (glufosinate or 2-amino-4-((hydroxy(methyl) phosphinyl) butyric acid ammonium salt (AHPB)), which is a structural analog of glutamate, is a recognized herbicide that acts on weeds through inhibition of glutamine synthetase. Due to the structural similarity between phosphinothricin and some bisphosphonates (BPs), this study focuses on investigating the possibility of repurposing phosphinothricin as a bisphosphonate analogue, particularly in two medicine-related activities: image probing and as an anti-cancer drug...
February 23, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Thorsten M Hoffmann, Emma Cwiklinski, Dinesh S Shah, Clare Stretton, Russell Hyde, Peter M Taylor, Harinder S Hundal
The SNAT2 (SLC38A2) System A amino acid transporter mediates Na+ -coupled cellular uptake of small neutral α-amino acids (AAs) and is extensively regulated in response to humoral and nutritional cues. Understanding the basis of such regulation is important given that AA uptake via SNAT2 has been linked to activation of mTORC1; a major controller of many important cellular processes including, for example, mRNA translation, lipid synthesis, and autophagy and whose dysregulation has been implicated in the development of cancer and conditions such as obesity and type 2 diabetes...
2018: Frontiers in Pharmacology
Karina N Gonzalez Herrera, Elma Zaganjor, Yoshinori Ishikawa, Jessica B Spinelli, Haejin Yoon, Jia-Ren Lin, F Kyle Satterstrom, Alison Ringel, Stacy Mulei, Amanda Souza, Joshua M Gorham, Craig C Benson, Jonathan G Seidman, Peter K Sorger, Clary B Clish, Marcia C Haigis
Sirtuin 3 (SIRT3) is a NAD+ -dependent deacetylase downregulated in aging and age-associated diseases such as cancer and neurodegeneration and in high-fat diet (HFD)-induced metabolic disorders. Here, we performed a small-molecule screen and identified an unexpected metabolic vulnerability associated with SIRT3 loss. Azaserine, a glutamine analog, was the top compound that inhibited growth and proliferation of cells lacking SIRT3. Using stable isotope tracing of glutamine, we observed its increased incorporation into de novo nucleotide synthesis in SIRT3 knockout (KO) cells...
February 20, 2018: Cell Reports
Alessandra Castegna, Alessio Menga
Glutamine synthetase (GS) is the adenosine triphosphate (ATP)-dependent enzyme that catalyses the synthesis of glutamine by condensing ammonium to glutamate. In the circulatory system, glutamine carries ammonia from muscle and brain to the kidney and liver. In brain reduction of GS activity has been suggested as a mechanism mediating neurotoxicity in neurodegenerative disorders. In cancer, the delicate balance between glutamine synthesis and catabolism is a critical event. In vitro evidence, confirmed in vivo in some cases, suggests that reduced GS activity in cancer cells associates with a more invasive and aggressive phenotype...
February 19, 2018: Genes
Marc-Olivier Turgeon, Nicholas J S Perry, George Poulogiannis
Although there has been a renewed interest in the field of cancer metabolism in the last decade, the link between metabolism and DNA damage/DNA repair in cancer has yet to be appreciably explored. In this review, we examine the evidence connecting DNA damage and repair mechanisms with cell metabolism through three principal links. (1) Regulation of methyl- and acetyl-group donors through different metabolic pathways can impact DNA folding and remodeling, an essential part of accurate double strand break repair...
2018: Frontiers in Oncology
Agnes Csanadi, Annika Oser, Konrad Aumann, Vera Gumpp, Justyna Rawluk, Ursula Nestle, Claudia Kayser, Sebastian Wiesemann, Martin Werner, Gian Kayser
Despite recent advances in therapeutic options, lung cancer is the leading cause of death among malignant diseases worldwide. Glutamine-dependence is an established attribute in cancer tissue with emerging importance as a diagnostic and therapeutic target. We analysed the expression of SLC1a5, a major glutamine transporter, in the primary tumour and corresponding nodal metastasis of non-small cell lung cancer (NSCLC) to investigate its biological impact. Expression of SLC1a5 was analysed by immunohistochemistry in 259 NSCLC and in 142 nodal metastases and correlated with clinicopathological parameters including overall survival...
February 15, 2018: Pathology
Marina Wright Muelas, Fernando Ortega, Rainer Breitling, Claus Bendtsen, Hans V Westerhoff
Optimization of experimental conditions is critical in ensuring robust experimental reproducibility. Through detailed metabolomic analysis we found that cell culture conditions significantly impacted on glutaminase (GLS1) sensitivity resulting in variable sensitivity and irreproducibility in data. Baseline metabolite profiling highlighted that untreated cells underwent significant changes in metabolic status. Both the extracellular levels of glutamine and lactate and the intracellular levels of multiple metabolites changed drastically during the assay...
February 14, 2018: Scientific Reports
Yaping Shao, Guozhu Ye, Shancheng Ren, Hai-Long Piao, Xinjie Zhao, Xin Lu, Fubo Wang, Ma Wang, Jia Li, Peiyuan Yin, Tian Xia, Chuanliang Xu, Jane J Yu, Yinghao Sun, Guowang Xu
Genetic alterations drive metabolic reprogramming to meet increased biosynthetic precursor and energy demands for cancer cell proliferation and survival in unfavorable environments. A systematic study of gene-metabolite regulatory networks and metabolic dysregulation should reveal the molecular mechanisms underlying prostate cancer (PCa) pathogenesis. Herein, we performed gas chromatography-mass spectrometry (GC-MS)-based metabolomics and RNA-seq analyses in prostate tumors and matched adjacent normal tissues (ANTs) to elucidate the molecular alterations and potential underlying regulatory mechanisms in PCa...
February 14, 2018: International Journal of Cancer. Journal International du Cancer
Ashish Kumar, Sagnik Giri, Chandrima Shaha
Differential utilization of metabolites and metabolic plasticity can confer adaptation to cancer cells under metabolic stress. Glutamine is one of the vital and versatile nutrients which cancer cells consume avidly for their proliferation, therefore, mechanisms related to glutamine metabolism has been identified as targets. Recently, SESN2 (sestrin2), a stress inducible protein has been reported to regulate survival in glutamine depleted cancer cells, based on this, we explored if SESN2 could regulate glutamine metabolism during glucose starvation...
February 12, 2018: FEBS Journal
Jianxin Ye, Qiang Huang, Jie Xu, Jinsheng Huang, Jinzhou Wang, Wenjing Zhong, Wannan Chen, Xinjian Lin, Xu Lin
PURPOSE: Glutamine (Gln) is essential for the proliferation of most cancer cells, making it an appealing target for cancer therapy. However, the role of Gln in gastric cancer (GC) metabolism is unknown and Gln-targeted therapy against GC remains scarce. The aim of this study was to investigate the relevance of Gln in GC growth and targeting. METHODS: Expression of Gln transporter ASCT2 and glutamine synthetase (GS) in the parental and molecularly engineered GC cells or in human GC specimens was determined by RT-PCR and western blot analysis or immunohistochemistry...
February 12, 2018: Journal of Cancer Research and Clinical Oncology
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