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Oncometabolite

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https://www.readbyqxmd.com/read/29202474/adhfe1-is-a-breast-cancer-oncogene-and-induces-metabolic-reprogramming
#1
Prachi Mishra, Wei Tang, Vasanta Putluri, Tiffany H Dorsey, Feng Jin, Fang Wang, Donewei Zhu, Lauren Amable, Tao Deng, Shaofei Zhang, J Keith Killian, Yonghong Wang, Tsion Z Minas, Harry G Yfantis, Dong H Lee, Arun Sreekumar, Michael Bustin, Wei Liu, Nagireddy Putluri, Stefan Ambs
Metabolic reprogramming in breast tumors is linked to increases in putative oncogenic metabolites that may contribute to malignant transformation. We previously showed that accumulation of the oncometabolite, 2-hydroxyglutarate (2HG), in breast tumors was associated with MYC signaling, but not with isocitrate dehydrogenase (IDH) mutations, suggesting a distinct mechanism for increased 2HG in breast cancer. Here, we determined that D-2HG is the predominant enantiomer in human breast tumors and show that the D-2HG-producing mitochondrial enzyme, alcohol dehydrogenase, iron-containing protein 1 (ADHFE1), is a breast cancer oncogene that decreases patient survival...
November 27, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29183865/intraventricular-glioblastoma-multiforme-in-a-child-with-l2-hydroxyglutaric-aciduria
#2
Ai Peng Tan, Kshitij Mankad
L2-hydroxyglutaric aciduria (L2-HGA) is a rare neurometabolic disease characterised by accumulation of L2-hydroxyglutarate (L2-HG), a potential oncometabolite resulting in significant lifetime risk for cerebral tumors. Here in, we present a case of intraventricular glioblastoma multiforme (GBM) in a 16-year-old child with L2-HGA who presented with rapid functional decline and persistent vomiting. The tumour was completely resected and the patient remained well at 2-year follow up. Clinicians should be aware of the usual insidious nature of the disease...
November 25, 2017: World Neurosurgery
https://www.readbyqxmd.com/read/29144447/bcat1-restricts-%C3%AE-kg-levels-in-aml-stem-cells-leading-to-idhmut-like-dna-hypermethylation
#3
Simon Raffel, Mattia Falcone, Niclas Kneisel, Jenny Hansson, Wei Wang, Christoph Lutz, Lars Bullinger, Gernot Poschet, Yannic Nonnenmacher, Andrea Barnert, Carsten Bahr, Petra Zeisberger, Adriana Przybylla, Markus Sohn, Martje Tönjes, Ayelet Erez, Lital Adler, Patrizia Jensen, Claudia Scholl, Stefan Fröhling, Sibylle Cocciardi, Patrick Wuchter, Christian Thiede, Anne Flörcken, Jörg Westermann, Gerhard Ehninger, Peter Lichter, Karsten Hiller, Rüdiger Hell, Carl Herrmann, Anthony D Ho, Jeroen Krijgsveld, Bernhard Radlwimmer, Andreas Trumpp
The branched-chain amino acid (BCAA) pathway and high levels of BCAA transaminase 1 (BCAT1) have recently been associated with aggressiveness in several cancer entities. However, the mechanistic role of BCAT1 in this process remains largely uncertain. Here, by performing high-resolution proteomic analysis of human acute myeloid leukaemia (AML) stem-cell and non-stem-cell populations, we find the BCAA pathway enriched and BCAT1 protein and transcripts overexpressed in leukaemia stem cells. We show that BCAT1, which transfers α-amino groups from BCAAs to α-ketoglutarate (αKG), is a critical regulator of intracellular αKG homeostasis...
November 16, 2017: Nature
https://www.readbyqxmd.com/read/29126125/highly-specific-determination-of-idh-status-using-edited-in-vivo-magnetic-resonance-spectroscopy
#4
Francesca Branzoli, Anna Luisa Di Stefano, Laurent Capelle, Chris Ottolenghi, Romain Valabrègue, Dinesh K Deelchand, Franck Bielle, Chiara Villa, Bertrand Baussart, Stéphane Lehéricy, Marc Sanson, Malgorzata Marjanska
Background: Mutations in the isocitrate dehydrogenase (IDH) enzyme affects 40% of gliomas and represent a major diagnostic and prognostic marker. The goals of this study were to evaluate the performance of noninvasive magnetic resonance spectroscopy (MRS) methods to determine the IDH status of patients with brain gliomas through detection of the oncometabolite 2-hydroxyglutarate (2HG), and to compare performance of these methods with DNA sequencing and tissue 2HG analysis. Methods: Twenty-four subjects with suspected diagnosis of low grade glioma were included prospectively in the study...
November 6, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/29105933/sarcosine-influences-apoptosis-and-growth-of-prostate-cells-via-cell-type-specific-regulation-of-distinct-sets-of-genes
#5
Miguel A Merlos Rodrigo, Vladislav Strmiska, Eva Horackova, Hana Buchtelova, Petr Michalek, Marie Stiborova, Tomas Eckschlager, Vojtech Adam, Zbynek Heger
BACKGROUND: Sarcosine is a widely discussed oncometabolite of prostate cells. Although several reports described connections between sarcosine and various phenotypic changes of prostate cancer (PCa) cells, there is still a lack of insights on the complex phenomena of its effects on gene expression patterns, particularly in non-malignant and non-metastatic cells. METHODS: To shed more light on this phenomenon, we performed parallel microarray profiling of RNA isolated from non-malignant (PNT1A), malignant (22Rv1), and metastatic (PC-3) prostate cell lines treated with sarcosine...
November 6, 2017: Prostate
https://www.readbyqxmd.com/read/29097607/adaptive-evolution-of-the-gdh2-allosteric-domain-promotes-gliomagenesis-by-resolving-idh1-r132h-induced-metabolic-liabilities
#6
Matthew S Waitkus, Christopher J Pirozzi, Casey J Moure, Bill H Diplas, Landon J Hansen, Austin B Carpenter, Rui Yang, Zhaohui Wang, Brian O Ingram, Edward D Karoly, Robert P Mohney, Ivan Spasojeic, Roger E McLendon, Henry S Friedman, Yiping He, Darell D Bigner, Hai Yan
Hot-spot mutations in the isocitrate dehydrogenase 1 (IDH1) gene occur in a number of human cancers and confer a neomorphic enzyme activity that catalyzes the conversion of α-ketoglutarate (αKG) to the oncometabolite D-(2)-hydroxyglutarate (D2HG). In malignant gliomas, IDH1(R132H) expression induces widespread metabolic reprogramming, possibly requiring compensatory mechanisms to sustain the normal biosynthetic requirements of actively proliferating tumor cells. We used genetically engineered mouse models of glioma and quantitative metabolomics to investigate IDH1(R132H)-dependent metabolic reprogramming and its potential to induce biosynthetic liabilities that can be exploited for glioma therapy...
November 2, 2017: Cancer Research
https://www.readbyqxmd.com/read/29090344/the-role-of-mutant-idh1-and-idh2-inhibitors-in-the-treatment-of-acute-myeloid-leukemia
#7
REVIEW
Samah Nassereddine, Coen J Lap, Faysal Haroun, Imad Tabbara
For decades, researchers have looked into the pathophysiology of acute myeloid leukemia (AML). With the advances in molecular techniques, the two-hit hypothesis was replaced by a multi-hit model, which also emphasizes the importance of aberrant epigenetic regulation in the pathogenesis of AML. IDH1 and IDH2 are two isoforms of isocitrate dehydrogenase that perform crucial roles in cellular metabolism. Somatic mutations in either of these two genes impart a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert α-ketoglutarate (αKG) into the oncometabolite R2-hydroxyglutarate (R2-HG), which can competitively inhibit multiple αKG-dependent dioxygenases...
December 2017: Annals of Hematology
https://www.readbyqxmd.com/read/29078321/identification-of-a-tumor-promoter-cholesterol-metabolite-in-human-breast-cancers-acting-through-the-glucocorticoid-receptor
#8
Maud Voisin, Philippe de Medina, Arnaud Mallinger, Florence Dalenc, Emilie Huc-Claustre, Julie Leignadier, Nizar Serhan, Régis Soules, Grégory Ségala, Aurélie Mougel, Emmanuel Noguer, Loubna Mhamdi, Elodie Bacquié, Luigi Iuliano, Chiara Zerbinati, Magali Lacroix-Triki, Léonor Chaltiel, Thomas Filleron, Vincent Cavaillès, Talal Al Saati, Philippe Rochaix, Raphaelle Duprez-Paumier, Camille Franchet, Laetitia Ligat, Fréderic Lopez, Michel Record, Marc Poirot, Sandrine Silvente-Poirot
Breast cancer (BC) remains the primary cause of death from cancer among women worldwide. Cholesterol-5,6-epoxide (5,6-EC) metabolism is deregulated in BC but the molecular origin of this is unknown. Here, we have identified an oncometabolism downstream of 5,6-EC that promotes BC progression independently of estrogen receptor α expression. We show that cholesterol epoxide hydrolase (ChEH) metabolizes 5,6-EC into cholestane-3β,5α,6β-triol, which is transformed into the oncometabolite 6-oxo-cholestan-3β,5α-diol (OCDO) by 11β-hydroxysteroid-dehydrogenase-type-2 (11βHSD2)...
October 31, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29057925/induction-of-synthetic-lethality-in-idh1-mutated-gliomas-through-inhibition-of-bcl-xl
#9
Georg Karpel-Massler, Chiaki Tsuge Ishida, Elena Bianchetti, Yiru Zhang, Chang Shu, Takashi Tsujiuchi, Matei A Banu, Franklin Garcia, Kevin A Roth, Jeffrey N Bruce, Peter Canoll, Markus D Siegelin
Certain gliomas often harbor a mutation in the activity center of IDH1 (R132H), which leads to the production of the oncometabolite 2-R-2-hydroxyglutarate (2-HG). In six model systems, including patient-derived stem cell-like glioblastoma cultures, inhibition of Bcl-xL induces significantly more apoptosis in IDH1-mutated cells than in wild-type IDH1 cells. Anaplastic astrocytoma samples with mutated IDH1 display lower levels of Mcl-1 than IDH1 wild-type tumors and specific knockdown of Mcl-1 broadly sensitizes glioblastoma cells to Bcl-xL inhibition-mediated apoptosis...
October 20, 2017: Nature Communications
https://www.readbyqxmd.com/read/29056515/in%C3%A2-vivo-imaging-of-glutamine-metabolism-to-the-oncometabolite-2-hydroxyglutarate-in-idh1-2-mutant-tumors
#10
Lucia Salamanca-Cardona, Hardik Shah, Alex J Poot, Fabian M Correa, Valentina Di Gialleonardo, Hui Lui, Vesselin Z Miloushev, Kristin L Granlund, Sui S Tee, Justin R Cross, Craig B Thompson, Kayvan R Keshari
The oncometabolite 2-hydroxyglutarate (2-HG) is a signature biomarker in various cancers, where it accumulates as a result of mutations in isocitrate dehydrogenase (IDH). The metabolic source of 2-HG, in a wide variety of cancers, dictates both its generation and also potential therapeutic strategies, but this remains difficult to access in vivo. Here, utilizing patient-derived chondrosarcoma cells harboring endogenous mutations in IDH1 and IDH2, we report that 2-HG can be rapidly generated from glutamine in vitro...
October 16, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/29054837/altered-metabolic-landscape-in-idh-mutant-gliomas%C3%A2-affects-phospholipid-energy-and-oxidative-stress-pathways
#11
Fred Fack, Saverio Tardito, Guillaume Hochart, Anais Oudin, Liang Zheng, Sabrina Fritah, Anna Golebiewska, Petr V Nazarov, Amandine Bernard, Ann-Christin Hau, Olivier Keunen, William Leenders, Morten Lund-Johansen, Jonathan Stauber, Eyal Gottlieb, Rolf Bjerkvig, Simone P Niclou
Heterozygous mutations in NADP-dependent isocitrate dehydrogenases (IDH) define the large majority of diffuse gliomas and are associated with hypermethylation of DNA and chromatin. The metabolic dysregulations imposed by these mutations, whether dependent or not on the oncometabolite D-2-hydroxyglutarate (D2HG), are less well understood. Here, we applied mass spectrometry imaging on intracranial patient-derived xenografts of IDH-mutant versus IDH wild-type glioma to profile the distribution of metabolites at high anatomical resolution in situ This approach was complemented by in vivo tracing of labeled nutrients followed by liquid chromatography-mass spectrometry (LC-MS) analysis...
October 20, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29038145/oncometabolites-a-new-paradigm-for-oncology-metabolism-and-the-clinical-laboratory
#12
REVIEW
Rebecca R J Collins, Khushbu Patel, William C Putnam, Payal Kapur, Dinesh Rakheja
BACKGROUND: Pediatric clinical laboratories commonly measure tricarboxylic acid cycle intermediates for screening, diagnosis, and monitoring of specific inborn errors of metabolism, such as organic acidurias. In the past decade, the same tricarboxylic acid cycle metabolites have been implicated and studied in cancer. The accumulation of these metabolites in certain cancers not only serves as a biomarker but also directly contributes to cellular transformation, therefore earning them the designation of oncometabolites...
October 16, 2017: Clinical Chemistry
https://www.readbyqxmd.com/read/28986582/assessing-inhibitors-of-mutant-isocitrate-dehydrogenase-using-a-suite-of-pre-clinical-discovery-assays
#13
Daniel J Urban, Natalia J Martinez, Mindy I Davis, Kyle R Brimacombe, Dorian M Cheff, Tobie D Lee, Mark J Henderson, Steven A Titus, Rajan Pragani, Jason M Rohde, Li Liu, Yuhong Fang, Surendra Karavadhi, Pranav Shah, Olivia W Lee, Amy Wang, Andrew McIver, Hongchao Zheng, Xiaodong Wang, Xin Xu, Ajit Jadhav, Anton Simeonov, Min Shen, Matthew B Boxer, Matthew D Hall
Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key metabolic enzymes that are mutated in a variety of cancers to confer a gain-of-function activity resulting in the accumulation of an oncometabolite, D-2-hydroxyglutarate (2-HG). Accumulation of 2-HG can result in epigenetic dysregulation and a block in cellular differentiation, suggesting these mutations play a role in neoplasia. Based on its potential as a cancer target, a number of small molecule inhibitors have been developed to specifically inhibit mutant forms of IDH (mIDH1 and mIDH2)...
October 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28984323/analysis-of-human-gliomas-by-swab-touch-spray-mass-spectrometry-applications-to-intraoperative-assessment-of-surgical-margins-and-presence-of-oncometabolites
#14
Valentina Pirro, Raquel Sero Llor, Alan K Jarmusch, Clint M Alfaro, Aaron A Cohen-Gadol, Eyas M Hattab, R Graham Cooks
Touch spray mass spectrometry using medical swabs is an ambient ionization technique (ionization of unprocessed sample in the open air) that has potential intraoperative application in quickly identifying the disease state of tissue and in better characterizing the resection margin. To explore this potential, we studied 29 human brain tumor specimens and obtained evidence that this technique can provide diagnostic molecular information that is relevant to brain cancer. Touch spray using medical swabs involves the physical sampling of tissue using a medical swab on a spatial scale of a few mm(2) with subsequent ionization occurring directly from the swab tip upon addition of solvent and application of a high voltage...
October 23, 2017: Analyst
https://www.readbyqxmd.com/read/28946040/hif-2alpha-achilles-heel-of-pseudohypoxic-subtype-paraganglioma-and-other-related-conditions
#15
Sri Harsha Tella, David Taïeb, Karel Pacak
Paragangliomas (PGLs) belong to the most hereditary endocrine tumours. The existence of mutated HIF2A in these tumours, the role of oncometabolites on HIFs stabilisation and a recent concept proposing how hereditary PGLs converge on the hypoxia-signalling pathway, brought solid evidence of the existence of PGL hypoxiom. Hypoxia-inducible factor 2alpha (HIF-2α) antagonists -PT2385, and PT2399 have been shown to have promising results in the management of clear cell renal cell carcinoma by targeting the HIF-2α pathway in recent and ongoing clinical trials (PT2799)...
September 22, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28916733/clonal-expansion-and-epigenetic-reprogramming-following-deletion-or-amplification-of-mutant-idh1
#16
Tali Mazor, Charles Chesnelong, Aleksandr Pankov, Llewellyn E Jalbert, Chibo Hong, Josie Hayes, Ivan V Smirnov, Roxanne Marshall, Camila F Souza, Yaoqing Shen, Pavithra Viswanath, Houtan Noushmehr, Sabrina M Ronen, Steven J M Jones, Marco A Marra, J Gregory Cairncross, Arie Perry, Sarah J Nelson, Susan M Chang, Andrew W Bollen, Annette M Molinaro, Henrik Bengtsson, Adam B Olshen, Samuel Weiss, Joanna J Phillips, H Artee Luchman, Joseph F Costello
IDH1 mutation is the earliest genetic alteration in low-grade gliomas (LGGs), but its role in tumor recurrence is unclear. Mutant IDH1 drives overproduction of the oncometabolite d-2-hydroxyglutarate (2HG) and a CpG island (CGI) hypermethylation phenotype (G-CIMP). To investigate the role of mutant IDH1 at recurrence, we performed a longitudinal analysis of 50 IDH1 mutant LGGs. We discovered six cases with copy number alterations (CNAs) at the IDH1 locus at recurrence. Deletion or amplification of IDH1 was followed by clonal expansion and recurrence at a higher grade...
October 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28914667/metabolic-regulation-of-macrophages-in-tumor-microenvironment
#17
Jaehong Kim, Jong-Sup Bae
PURPOSE OF REVIEW: Insight into the metabolic changes in cancer has become so important that cancer is regarded as a disease entity full of metabolic implications. We summarize the recent findings pertaining to cancer cell-derived metabolic changes that regulate the function of macrophages to favor cancer cell survival, and the reported approaches to reverse these changes. RECENT FINDINGS: Since the observation and dramatic revitalization of the Warburg effect, metabolic changes were thought to be confined in cancer cells...
September 13, 2017: Current Opinion in Hematology
https://www.readbyqxmd.com/read/28735490/measurement-of-oncometabolites-d-2-hydroxyglutaric-acid-and-l-2-hydroxyglutaric-acid
#18
Patricia M Jones, Richard Boriack, Eduard A Struys, Dinesh Rakheja
We describe a liquid chromatography-tandem mass spectrometry assay for measurement of D-2-hydroxyglutaric acid and L-2-hydroxyglutaric acid. These metabolites are increased in specific inborn errors of metabolism and are now recognized as oncometabolites. The measurement of D-2-hydroxyglutarate in peripheral blood may be used as a biomarker for screening and follow-up of patients with IDH-mutated acute myeloid leukemia.
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28711227/oncogenic-activities-of-idh1-2-mutations-from-epigenetics-to-cellular-signaling
#19
REVIEW
Laurence M Gagné, Karine Boulay, Ivan Topisirovic, Marc-Étienne Huot, Frédérick A Mallette
Gliomas and leukemias remain highly refractory to treatment, thus highlighting the need for new and improved therapeutic strategies. Mutations in genes encoding enzymes involved in the tricarboxylic acid (TCA) cycle, such as the isocitrate dehydrogenases 1 and 2 (IDH1/2), are frequently encountered in astrocytomas and secondary glioblastomas, as well as in acute myeloid leukemias; however, the precise molecular mechanisms by which these mutations promote tumorigenesis remain to be fully characterized. Gain-of-function mutations in IDH1/2 have been shown to stimulate production of the oncogenic metabolite R-2-hydroxyglutarate (R-2HG), which inhibits α-ketoglutarate (αKG)-dependent enzymes...
October 2017: Trends in Cell Biology
https://www.readbyqxmd.com/read/28705010/isocitrate-dehydrogenase-mutation-as-a-therapeutic-target-in-gliomas
#20
Catherine H Han, Tracy T Batchelor
Isocitrate dehydrogenases (IDH) are important enzymes that catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG), producing NADPH in the process. More than 80% of low-grade gliomas and secondary glioblastoma (GBM) harbor an IDH mutation. IDH mutations involve the catalytic pocket of the enzyme and lead to a neomorphic ability to produce 2-hydroxyglutarate (2HG) while oxidizing NADPH to NADP+. 2HG is considered as an 'oncometabolite' which is thought to be responsible for many, if not all, biologic effects of IDH mutations...
June 2017: Chinese Clinical Oncology
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