DOCSLIB.ORG

Exploiting Metabolic Vulnerabilities for Personalized Therapy in Acute Myeloid Leukemia Lucille Stuani, Marie Sabatier, Jean-Emmanuel Sarry

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Exploiting Metabolic Vulnerabilities for Personalized Therapy in Acute Myeloid Leukemia Lucille Stuani, Marie Sabatier, Jean-Emmanuel Sarry Exploiting metabolic vulnerabilities for personalized therapy in acute myeloid leukemia Lucille Stuani, Marie Sabatier, Jean-Emmanuel Sarry To cite this version: Lucille Stuani, Marie Sabatier, Jean-Emmanuel Sarry. Exploiting metabolic vulnerabilities for per- sonalized therapy in acute myeloid leukemia. BMC Biology, BioMed Central, 2019, 17 (1), pp.57. 10.1186/s12915-019-0670-4. inserm-02441720 HAL Id: inserm-02441720 https://www.hal.inserm.fr/inserm-02441720 Submitted on 16 Jan 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Stuani et al. BMC Biology (2019) 17:57 https://doi.org/10.1186/s12915-019-0670-4 REVIEW Open Access Exploiting metabolic vulnerabilities for personalized therapy in acute myeloid leukemia Lucille Stuani*, Marie Sabatier and Jean-Emmanuel Sarry* Therefore, more specific and safe therapeutics are ur- Abstract gently needed. One area of high interest and potential is Changes in cell metabolism and metabolic adaptation targeting metabolic and mitochondrial pathways that are are hallmark features of many cancers, including important in AML biology and that may constitute an leukemia, that support biological processes involved Achilles heel of AML cells. This review focuses on meta- into tumor initiation, growth, and response to bolic pathways dysregulated in AML, and especially in therapeutics. The discovery of mutations in key several cytogenetically defined patient subgroups, and metabolic enzymes has highlighted the importance of how targeting these metabolic dependencies impacts metabolism in cancer biology and how these changes proliferation and cell survival in this disease. might constitute an Achilles heel for cancer treatment. In this Review, we discuss the role of metabolic and Major metabolic dysregulations in acute myeloid mitochondrial pathways dysregulated in acute leukemia myeloid leukemia, and the potential of therapeutic Metabolism is altered in most, if not all, cancer cells, re- intervention targeting these metabolic dependencies gardless of the tumor type [4]. A key alteration in cancer on the proliferation, differentiation, stem cell function metabolism is the increase in glucose uptake required to and cell survival to improve patient stratification and satisfy energetic and anabolic demands. It is now well outcomes. established that the metabolic reprogramming under- gone by transformed cells extends far beyond glycolysis and the Warburg effect, and changes in cell metabolism Acute myeloid leukemia (AML) is a heterogeneous have fundamental implications for tumor biology and group of hematological malignancies and represents the therapy [5, 6]. most frequent cause of leukemia-related deaths [1]. It arises from genetic abnormalities in hematopoietic stem Glucose metabolism or progenitor cells, inducing uncontrolled growth and Higher aerobic glycolysis in cancer cells, reported almost an accumulation of abnormal myeloblasts, leading to one century ago by Otto Warburg and known as the bone marrow failure and often death. For the past three Warburg effect [7, 8], has sparked debate over the role decades, standard intensive induction therapy involved a of glycolysis and oxidative phosphorylation in normal combination of cytarabine plus anthracycline cytotoxic and cancer cells. Since Warburg’s discovery and espe- – chemotherapy. Despite a high rate (70 80%) of complete cially during the past 20 years, considerable efforts have remission after standard front-line chemotherapy, the been made to better understand glucose utilization in prognosis remains poor, especially for older patients. cancer cells, in particular to determine if inhibiting This mainly results from the high frequency of distant glycolysis or other glucose-dependent pathways could relapses caused by tumor regrowth initiated by chemore- represent promising therapeutic approaches. It has been sistant leukemic clones after chemotherapy [2, 3]. suggested that AML patients exhibit a high glycolytic metabolism at diagnosis that is potentially associated * Correspondence: [email protected]; [email protected] with favorable outcomes [9], even if the number of Centre de Recherches en Cancérologie de Toulouse, UMR1037, Inserm, patients in this study remains small. Another study re- Université de Toulouse 3 Paul Sabatier, Equipe Labellisée LIGUE 2018, ported that a six-metabolite signature (including F-31037 Toulouse, France © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Stuani et al. BMC Biology (2019) 17:57 Page 2 of 17 pyruvate and lactate) related to the crosstalk between glutamine by the SLC7A5/3A2 transporter and leucine is glycolysis and mitochondria was specifically enriched in required for Rheb-mediated mTOR activation at the lyso- the serum of patients at diagnosis compared to healthy somal surface [73, 74]. Glutamine is a non-essential amino controls and demonstrated prognostic value in cytoge- acid and one of the major carbon sources used by cancer netically normal AML (CN-AML) patients as it could cells for proliferation in vitro [75, 76]. It is also an import- predict poor survival for these patients [10]. Interest- ant nitrogen donor for amino acids and nucleotides and a ingly, deletions of the two glycolytic enzymes PKM2 and major substrate for TCA cycle intermediates as well as LDHA, which catalyze the production of cytosolic pyru- glutamate and aspartate [77–79](Fig.1). Dependence of vate and lactate, respectively, inhibit leukemia initiation leukemic cells on glutamine for tumor growth has been in vivo in AML mice models while preserving normal reported, and knockdown of the glutamine transporter hematopoietic stem cell function [11] (Fig. 1). SLC1A5 abrogates tumor development in mice [72]. Glucose metabolism is also involved in other crucial An approach to extend therapeutic opportunities metabolic pathways such as the pentose phosphate path- beyond glycolysis and glutaminolysis may be found way (PPP) coupled to NADPH production, glutathione/ in the identification of auxotrophic amino acids re- redox recycling, and nucleotide biosynthesis (Fig. 1). quired by AML cells. It has been reported that most Overexpression of glucose-6-phosphate dehydrogenase AML patients are deficient in arginosuccinate (G6PD) has been reported to correlate with an adverse synthetase-1 (ASS1), an enzyme that allows the con- prognosis in an AML cohort [12]. Moreover, in vitro version of citrulline and aspartate into the arginine and in vivo inhibition of 6-phosphogluconate dehydro- precursor argininosuccinate [29](Fig.1). The loss of genase (6PGD) and G6PD demonstrated anti-leukemic ASS1 has been reported in other tumor types where activities and synergized with cytarabine [12–15]. Inhib- it is required to support cell proliferation and nu- ition of 6PGD leads to impaired lipogenesis through re- cleotide synthesis by sustaining the intracellular as- activation of LKB1-AMPK signaling [14]. Sensitivity to partate level [80]. A decrease in ASS1 can also lead G6PD inhibition is driven by mTORC1 activity as to a dependence on arginine, which has been ex- mTORC1 activation leads to glucose addiction in AML. plored as a potential vulnerability in different cancer Inhibition of mTORC1 induces a switch toward oxida- types, including AML [29]. tive metabolism and survival of AML cells [12]. Further- more, the anti-leukemic effects of mTOR inhibitors are Lipid and sterol metabolism enhanced when combined with anti-glycolytic agents, De novo lipid biosynthesis is another metabolic pathway underscoring the strong interconnection between mTOR highly reprogrammed in cancer and leukemic cells, in activity and leukemic metabolism [16]. Better particular to increase biomass. Numerous studies sup- characterization of mTOR-associated metabolic alter- port targeting lipid synthesis for therapeutic benefit [81, ations would help in the design of new combinatory 82]. Inhibition of key lipogenic enzymes, fatty acid syn- therapeutic approaches and/or help distinguish patients thase (FASN) [83] and stearoyl CoA desaturase 1 who could better benefit from these treatments. This (SCD1) [68], have been shown to disrupt lipid synthesis will be even more important since no clear evidence of and induce apoptosis in AML (Fig. 1). SCD1 inhibition clinical efficacy has been found by several clinical trials was obtained through treatment with BaP, a combination of agents targeting mTOR kinase in myeloid leukemia of lipid-regulating bezafibrate and the sex hormone [17–22] (Table 1). This modest efficacy is due
Load more

Recommended publications
  • Ovulation-Selective Genes: the Generation and Characterization of an Ovulatory-Selective Cdna Library
    531 Ovulation-selective genes: the generation and characterization of an ovulatory-selective cDNA library A Hourvitz1,2*, E Gershon2*, J D Hennebold1, S Elizur2, E Maman2, C Brendle1, E Y Adashi1 and N Dekel2 1Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Utah Health Sciences Center, Salt Lake City, Utah 84132, USA 2Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel (Requests for offprints should be addressed to N Dekel; Email: [email protected]) *(A Hourvitz and E Gershon contributed equally to this paper) (J D Hennebold is now at Division of Reproductive Sciences, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon 97006, USA) Abstract Ovulation-selective/specific genes, that is, genes prefer- (FAE-1) homolog, found to be localized to the inner entially or exclusively expressed during the ovulatory periantral granulosa and to the cumulus granulosa cells of process, have been the subject of growing interest. We antral follicles. The FAE-1 gene is a -ketoacyl-CoA report herein studies on the use of suppression subtractive synthase belonging to the fatty acid elongase (ELO) hybridization (SSH) to construct a ‘forward’ ovulation- family, which catalyzes the initial step of very long-chain selective/specific cDNA library. In toto, 485 clones were fatty acid synthesis. All in all, the present study accom- sequenced and analyzed for homology to known genes plished systematic identification of those hormonally with the basic local alignment tool (BLAST). Of those, regulated genes that are expressed in the ovary in an 252 were determined to be nonredundant.
    [Show full text]
  • Isocitrate Dehydrogenase 1 (NADP+) (I5036)
    Isocitrate Dehydrogenase 1 (NADP+), human recombinant, expressed in Escherichia coli Catalog Number I5036 Storage Temperature –20 °C CAS RN 9028-48-2 IDH1 and IDH2 have frequent genetic alterations in EC 1.1.1.42 acute myeloid leukemia4 and better understanding of Systematic name: Isocitrate:NADP+ oxidoreductase these mutations may lead to an improvement of (decarboxylating) individual cancer risk assessment.6 In addition other studies have shown loss of IDH1 in bladder cancer Synonyms: IDH1, cytosolic NADP(+)-dependent patients during tumor development suggesting this may isocitrate dehydrogenase, isocitrate:NADP+ be involved in tumor progression and metastasis.7 oxidoreductase (decarboxylating), Isocitric Dehydrogenase, ICD1, PICD, IDPC, ICDC, This product is lyophilized from a solution containing oxalosuccinate decarboxylase Tris-HCl, pH 8.0, with trehalose, ammonium sulfate, and DTT. Product Description Isocitrate dehydrogenase (NADP+) [EC 1.1.1.42] is a Purity: ³90% (SDS-PAGE) Krebs cycle enzyme, which converts isocitrate to a-ketoglutarate. The flow of isocitrate through the Specific activity: ³80 units/mg protein glyoxylate bypass is regulated by phosphorylation of isocitrate dehydrogenase, which competes for a Unit definition: 1 unit corresponds to the amount of 1 common substrate (isocitrate) with isocitrate lyase. enzyme, which converts 1 mmole of DL-isocitrate to The activity of the enzyme is dependent on the a-ketoglutarate per minute at pH 7.4 and 37 °C (NADP formation of a magnesium or manganese-isocitrate as cofactor). The activity is measured by observing the 2 complex. reduction of NADP to NADPH at 340 nm in the 7 presence of 4 mM DL-isocitrate and 2 mM MnSO4.
    [Show full text]
  • NRF2 and the Ambiguous Consequences of Its Activation During Initiation and the Subsequent Stages of Tumourigenesis
    cancers Review NRF2 and the Ambiguous Consequences of Its Activation during Initiation and the Subsequent Stages of Tumourigenesis Holly Robertson 1,2, Albena T. Dinkova-Kostova 1 and John D. Hayes 1,* 1 Jacqui Wood Cancer Centre, Division of Cellular Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, UK; [email protected] (H.R.); [email protected] (A.T.D.-K.) 2 Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK * Correspondence: [email protected]; Tel.: +44-(0)-1382-383182 Received: 30 October 2020; Accepted: 27 November 2020; Published: 2 December 2020 Simple Summary: Transcription factor NRF2 controls expression of antioxidant and detoxification genes. Normally, the activity of NRF2 is tightly controlled in the cell, and is continuously adjusted to ensure that cells are protected against endogenous chemicals and environmental agents that perturb the intracellular antioxidant/pro-oxidant balance (i.e., redox) that must be maintained for them to grow and survive in an appropriate manner. This tight control of NRF2 is achieved by a repressor protein called KEAP1 that perpetually targets NRF2 protein for degradation under normal conditions, but is unable to do so when challenged with oxidants or thiol-reactive chemicals. In the context of cancer, it is well known that drugs that stimulate short-term and reversible activation of NRF2 can provide protection for a limited period against exposure to chemicals that cause cancer. However, it is also becoming widely recognised that permanent hyper-activation of NRF2 resulting from somatic mutations in the gene that encodes NRF2, or in genes associated with its degradation, is frequently observed in certain cancers and associated with poor outcome.
    [Show full text]
  • Energy Metabolism in IDH1 Wild-Type and IDH1-Mutated Glioblastoma Stem Cells: a Novel Target for Therapy?
    cells Review Energy Metabolism in IDH1 Wild-Type and IDH1-Mutated Glioblastoma Stem Cells: A Novel Target for Therapy? Cornelis J.F. van Noorden 1,2,*, Vashendriya V.V. Hira 1, Amber J. van Dijck 2 , Metka Novak 1, Barbara Breznik 1 and Remco J. Molenaar 1,3 1 Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, VeˇcnaPot 111, 1000 Ljubljana, Slovenia; [email protected] (V.V.V.H.); [email protected] (M.N.); [email protected] (B.B.); [email protected] (R.J.M.) 2 Department of Medical Biology, Amsterdam UMC Location Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; [email protected] 3 Department of Medical Oncology, Amsterdam UMC Location Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands * Correspondence: [email protected]; Tel.: +31-638-639-561 Abstract: Cancer is a redox disease. Low levels of reactive oxygen species (ROS) are beneficial for cells and have anti-cancer effects. ROS are produced in the mitochondria during ATP production by oxidative phosphorylation (OXPHOS). In the present review, we describe ATP production in primary brain tumors, glioblastoma, in relation to ROS production. Differentiated glioblastoma cells mainly use glycolysis for ATP production (aerobic glycolysis) without ROS production, whereas glioblastoma stem cells (GSCs) in hypoxic periarteriolar niches use OXPHOS for ATP and ROS production, which is modest because of the hypoxia and quiescence of GSCs. In a significant proportion of glioblastoma, Citation: van Noorden, C.J.F.; Hira, isocitrate dehydrogenase 1 (IDH1) is mutated, causing metabolic rewiring, and all cancer cells use V.V.V.; van Dijck, A.J.; Novak, M.; OXPHOS for ATP and ROS production.
    [Show full text]
  • Methylation-Dependent Tissue Factor Suppression Contributes to the Reduced Malignancy of IDH1 Mutant Gliomas
    Author Manuscript Published OnlineFirst on September 28, 2018; DOI: 10.1158/1078-0432.CCR-18-1222 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Unruh et al. Methylation-dependent Tissue Factor suppression contributes to the reduced malignancy of IDH1 mutant gliomas 1 1 2 1 1 Dusten Unruh, Snezana Mirkov, Brian Wray, Michael Drumm, Jonathan Lamano, Yuping D Li,1 Qazi F. Haider,1 Rodrigo Javier,1 Kathleen McCortney,1 Amanda Saratsis,1 Denise M. Scholtens,3 Jann N. Sarkaria,4 C. David James,1 Craig Horbinski1,5 1Department of Neurological Surgery, Northwestern University, Chicago, IL, 60611, USA 2Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL, 60611, USA 3Department of Preventive Medicine, Northwestern University, Chicago, IL, 60611, USA 4Department of Radiation Oncology, Mayo Clinic, Rochester, MN, 55905, USA 5Department of Pathology, Northwestern University, Chicago, IL, 60611, USA RUNNING TITLE Tissue Factor in IDH1mut and IDH1wt gliomas KEYWORDS Tissue Factor; glioma; isocitrate dehydrogenase; beta-catenin; protease-activated receptor FINANCIAL SUPPORT This work was supported by NIH grants K08CA155764 and R01NS102669 (C.H.). D.U. was supported by NIH grants T32CA070085 and F32CA216996. C.H., D.M.S., and C.D.J. were also supported by the Northwestern SPORE in Brain Cancer P50CA221747. The Mayo Clinic Brain Tumor Patient-Derived Xenograft National Resource is supported by Mayo Clinic, the Mayo SPORE in Brain Cancer P50CA108961 and NIH grant R24NS92940. Histology and fluorescent 1 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 28, 2018; DOI: 10.1158/1078-0432.CCR-18-1222 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
    [Show full text]
  • Computational Inferences of Mutations Driving Mesenchymal Differentiation in Glioblastoma
    Computational Inferences of Mutations Driving Mesenchymal Differentiation in Glioblastoma James Chen Submitted in partial fulfillment of the requirements for the Doctor of Philosophy Degree in the Graduate School of Arts and Sciences Columbia University 2013 ! 2013 James Chen All rights reserved ABSTRACT Computational Inferences of Mutations Driving Mesenchymal Differentiation in Glioblastoma James Chen This dissertation reviews the development and implementation of integrative, systems biology methods designed to parse driver mutations from high- throughput array data derived from human patients. The analysis of vast amounts of genomic and genetic data in the context of complex human genetic diseases such as Glioblastoma is a daunting task. Mutations exist by the hundreds, if not thousands, and only an unknown handful will contribute to the disease in a significant way. The goal of this project was to develop novel computational methods to identify candidate mutations from these data that drive the molecular differentiation of glioblastoma into the mesenchymal subtype, the most aggressive, poorest-prognosis tumors associated with glioblastoma. TABLE OF CONTENTS CHAPTER 1… Introduction and Background 1 Glioblastoma and the Mesenchymal Subtype 3 Systems Biology and Master Regulators 9 Thesis Project: Genetics and Genomics 20 CHAPTER 2… TCGA Data Processing 23 CHAPTER 3… DIGGIn Part 1 – Selecting f-CNVs 33 Mutual Information 40 Application and Analysis 45 CHAPTER 4… DIGGIn Part 2 – Selecting drivers 52 CHAPTER 5… KLHL9 Manuscript 63 Methods 90 CHAPTER 5a… Revisions work-in-progress 105 CHAPTER 6… Discussion 109 APPENDICES… 132 APPEND01 – TCGA classifications 133 APPEND02 – GBM f-CNV list 136 APPEND03 – MES f-CNV candidate drivers 152 APPEND04 – Scripts 149 APPEND05 – Manuscript Figures and Legends 175 APPEND06 – Manuscript Supplemental Materials 185 i ACKNOWLEDGEMENTS I would like to thank the Califano Lab and my mentor, Andrea Califano, for their intellectual and motivational support during my stay in their lab.
    [Show full text]
  • Wild-Type and Mutated IDH1/2 Enzymes and Therapy Responses
    Oncogene (2018) 37:1949–1960 https://doi.org/10.1038/s41388-017-0077-z REVIEW ARTICLE Corrected: Correction Wild-type and mutated IDH1/2 enzymes and therapy responses 1,2,3 3 2 1 Remco J. Molenaar ● Jaroslaw P. Maciejewski ● Johanna W. Wilmink ● Cornelis J.F. van Noorden Received: 22 September 2017 / Revised: 2 November 2017 / Accepted: 7 November 2017 / Published online: 25 January 2018 © The Author(s) 2018. This article is published with open access Abstract Isocitrate dehydrogenase 1 and 2 (IDH1/2) are key enzymes in cellular metabolism, epigenetic regulation, redox states, and DNA repair. IDH1/2 mutations are causal in the development and/or progression of various types of cancer due to supraphysiological production of D-2-hydroxyglutarate. In various tumor types, IDH1/2-mutated cancers predict for improved responses to treatment with irradiation or chemotherapy. The present review discusses the molecular basis of the sensitivity of IDH1/2-mutated cancers with respect to the function of mutated IDH1/2 in cellular processes and their interactions with novel IDH1/2-mutant inhibitors. Finally, lessons learned from IDH1/2 mutations for future clinical applications in IDH1/2 wild-type cancers are discussed. 1234567890();,: Introduction production of D-2HG is essentially a gain of function that is exclusive to mutant IDH1/2 enzymes, it was quickly rea- Isocitrate dehydrogenase 1 and 2 (IDH1/2) are key enzymes lized that these frequently-occurring genetic alterations that function at a crossroads of cellular metabolism, epi- were promising targets for personalized anti-cancer therapy genetic regulation, redox states, and DNA repair. Mutations with small-molecule inhibitors [13].
    [Show full text]
  • BCAT1 Expression Associates with Ovarian Cancer Progression: Possible Implications in Altered Disease Metabolism
    www.impactjournals.com/oncotarget/ Oncotarget, Vol. 6, No. 31 BCAT1 expression associates with ovarian cancer progression: possible implications in altered disease metabolism Zhi-Qiang Wang1,2, Adnen Faddaoui1,2, Magdalena Bachvarova2, Marie Plante2,3, Jean Gregoire2,3, Marie-Claude Renaud2,3, Alexandra Sebastianelli2,3, Chantal Guillemette4,5, Stéphane Gobeil1,4, Elizabeth Macdonald6, Barbara Vanderhyden6, Dimcho Bachvarov1,2 1Department of Molecular Medicine, Laval University, Québec PQ, Canada 2Centre de recherche du CHU de Québec, L’Hôtel-Dieu de Québec, Québec PQ, Canada 3Department of Obstetrics and Gynecology, Laval University, Québec PQ, Canada 4Centre de recherche du CHU de Québec, CHUL, Québec PQ, Canada 5Faculty of Pharmacy, Laval University, Québec PQ, Canada 6Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada Correspondence to: Dimcho Bachvarov, e-mail: [email protected] Keywords: BCAT1, ovarian cancer, cancer metabolism, metastasis, DNA hypomethylation Received: May 07, 2015 Accepted: August 28, 2015 Published: September 10, 2015 ABSTRACT Previously, we have identified the branched chain amino-acid transaminase 1 (BCAT1) gene as notably hypomethylated in low-malignant potential (LMP) and high-grade (HG) serous epithelial ovarian tumors, compared to normal ovarian tissues. Here we show that BCAT1 is strongly overexpressed in both LMP and HG serous epithelial ovarian tumors, which probably correlates with its hypomethylated status. Knockdown of the BCAT1 expression in epithelial ovarian cancer (EOC) cells led to sharp decrease of cell proliferation, migration and invasion and inhibited cell cycle progression. BCAT1 silencing was associated with the suppression of numerous genes and pathways known previously to be implicated in ovarian tumorigenesis, and the induction of some tumor suppressor genes (TSGs).
    [Show full text]
  • (IDH1) Helps Regulate Catalysis and Ph Sensitivity
    bioRxiv preprint doi: https://doi.org/10.1101/2020.04.19.049387; this version posted April 20, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Mechanisms of pH-dependent IDH1 catalysis An acidic residue buried in the dimer interface of isocitrate dehydrogenase 1 (IDH1) helps regulate catalysis and pH sensitivity Lucas A. Luna1, Zachary Lesecq1, Katharine A. White2, An Hoang1, David A. Scott3, Olga Zagnitko3, Andrey A. Bobkov3, Diane L. Barber4, Jamie M. Schiffer5, Daniel G. Isom6, and Christal D. Sohl1,‡,§ From the 1Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA, 92182; 2Harper Cancer Research Institute, Department of Chemistry and Biochemistry, University of Notre Dame, South Bend, IN, 46617; 3Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037; 4Department of Cell and Tissue Biology, University of California, San Francisco, CA, 94143; 5Janssen Research and Development, 3210 Merryfield Row, San Diego, CA, 92121; 6Department of Pharmacology, Sylvester Comprehensive Cancer Center, and Center for Computational Sciences, University of Miami, Miami, FL, 33136 Running title: Mechanisms of pH-dependent IDH1 catalysis ‡To whom correspondence should be addressed: Christal D. Sohl, Department of Chemistry and Biochemistry, San Diego State University, CSL 328, 5500 Campanile Dr., San Diego, California 92182, Email: [email protected]; Telephone: (619) 594-2053. §This paper is dedicated to the memory of our dear colleague and friend, Michelle Evon Scott (1990-2020). Keywords: enzyme kinetics, cancer, tumor metabolism, pH regulation, post-translational modification (PTM), buried ionizable residues ABSTRACT protonation states leading to conformational Isocitrate dehydrogenase 1 (IDH1) changes that regulate catalysis.
    [Show full text]
  • Integrated Analysis of Cancer Stem Cells-Associated Lncrna-Mirna-Mrna Network for Ovarian Cancer Via Microarray and Gene Expression Omnibus Database
    Integrated analysis of cancer stem cells-associated lncRNA-miRNA-mRNA network for ovarian cancer via microarray and Gene Expression Omnibus database Zheng Li Shengjing Hospital of China Medical University Zhijiao Wang Shengjing Hospital of China Medical University Yingying Zhou ( [email protected] ) Shengjing Hospital of China Medical University https://orcid.org/0000-0002-8098-1632 Research Keywords: Ovarian cancer stem cells (OCSCs), Competing endogenous RNAs (ceRNAs), MiR-146a-5p, LINC006654, NRP2. Posted Date: November 13th, 2020 DOI: https://doi.org/10.21203/rs.3.rs-106454/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/39 Abstract Background: Cancer stem cells (CSCs) are associated with the recurrence, metastasis and chemoresistance of epithelial ovarian cancer. Competing endogenous RNAs (CeRNAs) play an important role in maintenance of ovarian cancer stem cell-like cells (OCSCs) characteristics. To construct a ceRNA regulatory network for OCSCs, microarray technology and Gene Expression Omnibus (GEO) database had been used. Human serous epithelial ovarian carcinoma cell line COC1 cells were treated with cisplatin and paclitaxel then maintained in stem cell conditions for 6 days to obtain CD117+/CD133+ cells (OCSCs). We identied the differentially expressed miRNAs (DEMs), lncRNA (DELs) and mRNA (DEGs) between OCSCs and COC1 by microarray and combined them with representative microarray proles in GEO Database. Results: According to the combination, 28 DEMs were identied at rst, and 452 DEGs were obtained combining with the predicted targets of these miRNAs and our mRNA microarray results. Up-regulated DEGs of them were signicantly enriched in ‘p53 signaling pathway’, ‘FoxO signaling pathway’ and ‘MicroRNAs in cancer’, whereas down-regulated DEGs were signicantly enriched in ‘Adherens junction’ and ‘Hepatitis C’ pathway.
    [Show full text]
  • Molecular and Functional Analyses of Mutant Idh1 in Murine Neural Stem and Progenitor Cells
    Molecular and functional analyses of mutant Idh1 in murine neural stem and progenitor cells Inaugural-Dissertation zur Erlangung des Doktorgrades der Mathematisch-Naturwissenschaftlichen Fakultät der Heinrich-Heine-Universität Düsseldorf vorgelegt von Miriam Knühmann aus Kamp-Lintfort Düsseldorf, April 2019 aus dem Institut für Neuropathologie der Heinrich-Heine-Universität Düsseldorf Gedruckt mit der Genehmigung der Mathematisch-Naturwissenschaftlichen Fakultät der Heinrich-Heine-Universität Düsseldorf Referent: Prof. Dr. med. Guido Reifenberger Koreferent: Prof. Dr. Andreas Weber Tag der mündlichen Prüfung: 05.Juli 2019 • FOR MY FAMILY • “IT DOESN’T MATTER IF YOU FALL DOWN AS LONG AS YOU PICK SOMETHING UP FROM THE FLOOR WHEN YOU GET UP.” EFRAIM RACKER I. CONTENTS I. CONTENTS I. Contents ....................................................................................................................... 1 II. Abbreviations .............................................................................................................. 5 III. SI units .......................................................................................................................10 IV. Zusammenfassung ...................................................................................................11 V. Summary ....................................................................................................................12 1.0 Introduction ..............................................................................................................13
    [Show full text]
  • Functional and Topographic Effects on DNA Methylation in IDH1/2 Mutant
    www.nature.com/scientificreports OPEN Functional and topographic efects on DNA methylation in IDH1/2 mutant cancers Ramona Bledea1, Varshini Vasudevaraja1, Seema Patel1, James Staford2, Jonathan Serrano1, Gianna Esposito1, Lilian M. Tredwin1, Nina Goodman1, Andreas Kloetgen1, John G. Golfnos3, David Zagzag1,3, Britta Weigelt4, A. John Iafrate5, Erik P. Sulman 6, Andrew S. Chi7, Snjezana Dogan4, Jorge S. Reis-Filho 4, Sarah Chiang4, Dimitris Placantonakis3,7,8,9, Aristotelis Tsirigos 1,7 & Matija Snuderl1,7* IDH1/2 mutations are early drivers present in diverse human cancer types arising in various tissue sites. IDH1/2 mutation is known to induce a global hypermethylator phenotype. However, the efects on DNA methylation across IDH mutant cancers and functionally diferent genome regions, remain unknown. We analyzed DNA methylation data from IDH1/2 mutant acute myeloid leukemia, oligodendroglioma, astrocytoma, solid papillary breast carcinoma with reverse polarity, sinonasal undiferentiated carcinoma and cholangiocarcinoma, which clustered by their embryonal origin. Hypermethylated common probes afect predominantly gene bodies while promoters in IDH1/2 mutant cancers remain unmethylated. Enhancers showed global hypermethylation, however commonly hypomethylated enhancers were associated with tissue diferentiation and cell fate determination. We demonstrate that some chromosomes, chromosomal arms and chromosomal regions are more afected by IDH1/2 mutations while others remain resistant to IDH1/2 mutation induced methylation changes. Therefore IDH1/2 mutations have diferent methylation efect on diferent parts of the genome, which may be regulated by diferent mechanisms. The Isocitrate dehydrogenase (IDH) gene family is composed of three genes, IDH1, IDH2 and IDH3. IDH enzymes catalyze oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG) in the citric acid cycle.
    [Show full text]