Functional Genomics Reveals Synthetic Lethality between Phosphogluconate Dehydrogenase and Oxidative Phosphorylation.

Animals Cell Line, Tumor Female Fumarate Hydratase / genetics Genomics / methods Glycolysis Humans Loss of Function Mutation Mice Mice, Nude Oxidative Phosphorylation Phosphogluconate Dehydrogenase / genetics Synthetic Lethal Mutations
OXPHOS PGD fumarate hydratase functional genomics hereditary leiomyomatosis renal cell carcinoma metabolic vulnerability pentose phosphate pathway redox homeostasis synthetic lethality tumor metabolism

Journal

Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691

Informations de publication

Date de publication:
08 01 2019
Historique:
received: 19 08 2017
revised: 19 07 2018
accepted: 10 12 2018
entrez: 10 1 2019
pubmed: 10 1 2019
medline: 15 2 2020
Statut: ppublish

Résumé

The plasticity of a preexisting regulatory circuit compromises the effectiveness of targeted therapies, and leveraging genetic vulnerabilities in cancer cells may overcome such adaptations. Hereditary leiomyomatosis renal cell carcinoma (HLRCC) is characterized by oxidative phosphorylation (OXPHOS) deficiency caused by fumarate hydratase (FH) nullizyogosity. To identify metabolic genes that are synthetically lethal with OXPHOS deficiency, we conducted a genetic loss-of-function screen and found that phosphogluconate dehydrogenase (PGD) inhibition robustly blocks the proliferation of FH mutant cancer cells both in vitro and in vivo. Mechanistically, PGD inhibition blocks glycolysis, suppresses reductive carboxylation of glutamine, and increases the NADP

Identifiants

DOI: 10.1016/j.celrep.2018.12.043 PMID: 30625329
pubmed: 30625329
pii: S2211-1247(18)31973-9
doi: 10.1016/j.celrep.2018.12.043
pii:
doi:

Substances chimiques

Phosphogluconate Dehydrogenase EC 1.1.1.43
Fumarate Hydratase EC 4.2.1.2

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

469-482.e5

Subventions

Organisme : NCI NIH HHS
ID : P50 CA127001
Pays : United States
Organisme : NIH HHS
ID : S10 OD012304
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States

Informations de copyright

Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Auteurs

Yuting Sun (Y)

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: ysun8@mdanderson.org.

Madhavi Bandi (M)

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Timothy Lofton (T)

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Melinda Smith (M)

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Christopher A Bristow (CA)

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Alessandro Carugo (A)

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Norma Rogers (N)

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Paul Leonard (P)

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Qing Chang (Q)

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Robert Mullinax (R)

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Jing Han (J)

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Xi Shi (X)

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Sahil Seth (S)

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Brooke A Meyers (BA)

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Meredith Miller (M)

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Lili Miao (L)

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Xiaoyan Ma (X)

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Ningping Feng (N)

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Virginia Giuliani (V)

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Mary Geck Do (M)

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Barbara Czako (B)

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Wylie S Palmer (WS)

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Faika Mseeh (F)

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

John M Asara (JM)

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

Yongying Jiang (Y)

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Pietro Morlacchi (P)

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Shuping Zhao (S)

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Michael Peoples (M)

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Trang N Tieu (TN)

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Marc O Warmoes (MO)

Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Philip L Lorenzi (PL)

Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Florian L Muller (FL)

Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Ronald A DePinho (RA)

Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Giulio F Draetta (GF)

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Carlo Toniatti (C)

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Philip Jones (P)

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Timothy P Heffernan (TP)

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Joseph R Marszalek (JR)

Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: jrmarszalek@mdanderson.org.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Functional Genomics Reveals Synthetic...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Functional Genomics Reveals Synthetic...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Lyases › Carbon-oxygen lyases › Hydro-lyases › Fumarate hydratase › Functional Genomics Reveals Synthetic...
questionsmedicales.fr › Disciplines des sciences naturelles › Disciplines des sciences biologiques › Biologie › Génétique › Génomique › Functional Genomics Reveals Synthetic...
questionsmedicales.fr › Métabolisme › Voies et réseaux métaboliques › Glycolyse › Functional Genomics Reveals Synthetic...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Functional Genomics Reveals Synthetic...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Mutation perte de fonction › Functional Genomics Reveals Synthetic...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Functional Genomics Reveals Synthetic...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souches mutantes de souris › Souris nude › Functional Genomics Reveals Synthetic...
questionsmedicales.fr › Métabolisme › Phosphorylation › Phosphorylation oxydative › Functional Genomics Reveals Synthetic...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Oxidoreductases › Alcohol oxidoreductases › Carbohydrate dehydrogenases › Phosphogluconate dehydrogenase › Functional Genomics Reveals Synthetic...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Mutations synthétiques létales › Functional Genomics Reveals Synthetic...