Glutamine Anabolism Plays a Critical Role in Pancreatic Cancer by Coupling Carbon and Nitrogen Metabolism.
Animals
Carbon
/ metabolism
Carcinoma, Pancreatic Ductal
/ enzymology
Cell Line, Tumor
Cell Proliferation
Female
Gene Deletion
Glutamate-Ammonia Ligase
/ antagonists & inhibitors
Glutamine
/ metabolism
Humans
Ketoglutaric Acids
/ metabolism
Male
Mice, Inbred C57BL
Nitrogen
/ metabolism
Pancreatic Neoplasms
/ enzymology
K-Ras
glutamate ammonia ligase
glutamine
glutamine synthetase
hexosamine
nitrogen metabolism
nucleotide
pancreatic cancer
α-ketoglutarate
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
29 10 2019
29 10 2019
Historique:
received:
22
12
2018
revised:
20
06
2019
accepted:
17
09
2019
entrez:
31
10
2019
pubmed:
31
10
2019
medline:
26
9
2020
Statut:
ppublish
Résumé
Glutamine is thought to play an important role in cancer cells by being deaminated via glutaminolysis to α-ketoglutarate (aKG) to fuel the tricarboxylic acid (TCA) cycle. Supporting this notion, aKG supplementation can restore growth/survival of glutamine-deprived cells. However, pancreatic cancers are often poorly vascularized and limited in glutamine supply, in alignment with recent concerns on the significance of glutaminolysis in pancreatic cancer. Here, we show that aKG-mediated rescue of glutamine-deprived pancreatic ductal carcinoma (PDAC) cells requires glutamate ammonia ligase (GLUL), the enzyme responsible for de novo glutamine synthesis. GLUL-deficient PDAC cells are capable of the TCA cycle but defective in aKG-coupled glutamine biosynthesis and subsequent nitrogen anabolic processes. Importantly, GLUL expression is elevated in pancreatic cancer patient samples and in mouse PDAC models. GLUL ablation suppresses the development of Kras
Identifiants
pubmed: 31665640
pii: S2211-1247(19)31244-6
doi: 10.1016/j.celrep.2019.09.056
pmc: PMC6886125
mid: NIHMS1542675
pii:
doi:
Substances chimiques
Ketoglutaric Acids
0
Glutamine
0RH81L854J
Carbon
7440-44-0
Glutamate-Ammonia Ligase
EC 6.3.1.2
Nitrogen
N762921K75
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1287-1298.e6Subventions
Organisme : NCI NIH HHS
ID : F99 CA212445
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA224550
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA188134
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA101955
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA190092
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA205172
Pays : United States
Organisme : NCI NIH HHS
ID : P20 CA192994
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA215059
Pays : United States
Organisme : NCI NIH HHS
ID : K22 CA190521
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA045508
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK109714
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA180944
Pays : United States
Organisme : NCI NIH HHS
ID : P20 CA192996
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA129536
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA232246
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA210240
Pays : United States
Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
Références
Tumour Biol. 2016 Feb;37(2):1541-58
pubmed: 26700676
Cell Metab. 2016 Mar 8;23(3):517-28
pubmed: 26853747
Cancer Cell. 2005 May;7(5):469-83
pubmed: 15894267
Nature. 2011 Nov 20;481(7381):385-8
pubmed: 22101431
Nature. 2017 Nov 2;551(7678):115-118
pubmed: 29045397
Cell. 2017 Aug 24;170(5):875-888.e20
pubmed: 28757253
J Appl Physiol. 1974 Jun;36(6):693-7
pubmed: 4829908
PLoS Biol. 2017 Nov 6;15(11):e2002810
pubmed: 29107960
Nature. 2009 Apr 9;458(7239):762-5
pubmed: 19219026
Oncogene. 2010 Jan 21;29(3):313-24
pubmed: 19881548
Anal Chem. 2017 Jun 6;89(11):5940-5948
pubmed: 28471646
Anal Chem. 2010 Dec 1;82(23):9818-26
pubmed: 21049934
Nat Commun. 2017 Jul 03;8:15965
pubmed: 28671190
J Biol Chem. 2010 Mar 26;285(13):9516-24
pubmed: 20064933
Nature. 2016 Aug 25;536(7617):479-83
pubmed: 27509858
Science. 2015 Jan 23;347(6220):1260419
pubmed: 25613900
Trends Cancer. 2017 Mar;3(3):169-180
pubmed: 28393116
Nature. 2018 Nov;563(7732):569-573
pubmed: 30429607
Nat Cell Biol. 2016 Aug;18(8):886-896
pubmed: 27428308
Cell Metab. 2012 Jun 6;15(6):827-37
pubmed: 22682223
Nat Cell Biol. 2015 Dec;17(12):1556-68
pubmed: 26595383
Genes Dev. 2011 Mar 1;25(5):460-70
pubmed: 21317241
Cell Metab. 2019 Feb 5;29(2):417-429.e4
pubmed: 30449684
NMR Biomed. 2012 Nov;25(11):1234-44
pubmed: 22419606
Nat Cell Biol. 2018 May;20(5):597-609
pubmed: 29662176
Cell. 2015 Jan 15;160(1-2):324-38
pubmed: 25557080
Nature. 2018 Sep;561(7721):63-69
pubmed: 30158707
Cancer Cell. 2018 Nov 12;34(5):724-740.e4
pubmed: 30423294
J Clin Invest. 2013 Sep;123(9):3678-84
pubmed: 23999442
Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):5947-52
pubmed: 16585505
Cancer Res. 2015 Sep 1;75(17):3529-42
pubmed: 26330165
Neoplasia. 1999 Apr;1(1):50-62
pubmed: 10935470
Trends Biochem Sci. 2010 Aug;35(8):427-33
pubmed: 20570523
PLoS One. 2013 Nov 20;8(11):e80580
pubmed: 24278292
Proc Natl Acad Sci U S A. 2008 Dec 2;105(48):18782-7
pubmed: 19033189
Cell. 2014 Dec 18;159(7):1603-14
pubmed: 25525878
Cell Metab. 2015 Dec 1;22(6):1068-77
pubmed: 26603296
Science. 2017 Nov 17;358(6365):941-946
pubmed: 29025995
Cell Metab. 2018 Nov 6;28(5):721-736.e6
pubmed: 30122553
Genes Dev. 2012 May 1;26(9):877-90
pubmed: 22549953
Nature. 2013 Apr 4;496(7443):101-5
pubmed: 23535601
Nat Rev Cancer. 2016 Oct;16(10):619-34
pubmed: 27492215
Genes Dev. 2001 Dec 15;15(24):3243-8
pubmed: 11751630
Nature. 2015 Feb 19;518(7539):413-6
pubmed: 25487152
Cancer Res. 2015 Feb 1;75(3):544-53
pubmed: 25644265
Cell Metab. 2016 Nov 8;24(5):685-700
pubmed: 27829138