Inhibiting Glutamine-Dependent mTORC1 Activation Ameliorates Liver Cancers Driven by β-Catenin Mutations.
Acetates
/ pharmacology
Animals
Carcinoma, Hepatocellular
/ drug therapy
Cell Line, Tumor
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
Child
Child, Preschool
Disease Models, Animal
Female
Glutamate-Ammonia Ligase
/ genetics
Glutamine
/ metabolism
Hepatocytes
/ metabolism
Humans
Infant
Liver Neoplasms
/ drug therapy
Male
Mechanistic Target of Rapamycin Complex 1
/ antagonists & inhibitors
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutation
Phenols
/ pharmacology
Retrospective Studies
Sirolimus
/ pharmacology
TOR Serine-Threonine Kinases
/ genetics
Transfection
Wnt Signaling Pathway
/ genetics
beta Catenin
/ genetics
Wnt
beta-catenin
glutamine synthetase
hepatocellular cancer
liver tumor
mTOR
metabolic zonation
personalized medicine
precision therapy
tumor metabolism
Journal
Cell metabolism
ISSN: 1932-7420
Titre abrégé: Cell Metab
Pays: United States
ID NLM: 101233170
Informations de publication
Date de publication:
07 05 2019
07 05 2019
Historique:
received:
01
11
2018
revised:
03
12
2018
accepted:
07
01
2019
pubmed:
5
2
2019
medline:
14
7
2020
entrez:
5
2
2019
Statut:
ppublish
Résumé
Based on their lobule location, hepatocytes display differential gene expression, including pericentral hepatocytes that surround the central vein, which are marked by Wnt-β-catenin signaling. Activating β-catenin mutations occur in a variety of liver tumors, including hepatocellular carcinoma (HCC), but no specific therapies are available to treat these tumor subsets. Here, we identify a positive relationship between β-catenin activation, its transcriptional target glutamine synthetase (GS), and p-mTOR-S2448, an indicator of mTORC1 activation. In normal livers of mice and humans, pericentral hepatocytes were simultaneously GS and p-mTOR-S2448 positive, as were β-catenin-mutated liver tumors. Genetic disruption of β-catenin signaling or GS prevented p-mTOR-S2448 expression, while its forced expression in β-catenin-deficient livers led to ectopic p-mTOR-S2448 expression. Further, we found notable therapeutic benefit of mTORC1 inhibition in mutant-β-catenin-driven HCC through suppression of cell proliferation and survival. Thus, mTORC1 inhibitors could be highly relevant in the treatment of liver tumors that are β-catenin mutated and GS positive.
Identifiants
pubmed: 30713111
pii: S1550-4131(19)30002-6
doi: 10.1016/j.cmet.2019.01.002
pmc: PMC6506359
mid: NIHMS1518395
pii:
doi:
Substances chimiques
Acetates
0
CTNNB1 protein, human
0
CTNNB1 protein, mouse
0
GC 1 compound
0
Phenols
0
beta Catenin
0
Glutamine
0RH81L854J
MTOR protein, human
EC 2.7.1.1
Mechanistic Target of Rapamycin Complex 1
EC 2.7.11.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
Glutamate-Ammonia Ligase
EC 6.3.1.2
Sirolimus
W36ZG6FT64
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
1135-1150.e6Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK101426
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK116993
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA186873
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK062277
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA204586
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK109365
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA136606
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK100287
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
Références
Trends Cell Biol. 2016 Dec;26(12):918-933
pubmed: 27426745
BMC Cancer. 2018 Nov 12;18(1):1093
pubmed: 30419856
Transplantation. 2016 Jan;100(1):116-25
pubmed: 26555945
Carcinogenesis. 2005 Jan;26(1):239-48
pubmed: 15471898
Am J Pathol. 2017 Nov;187(11):2473-2485
pubmed: 28807594
Proc Natl Acad Sci U S A. 2015 Apr 28;112(17):5521-6
pubmed: 25870278
Nat Genet. 2015 May;47(5):505-511
pubmed: 25822088
Cell. 2017 Jun 1;169(6):985-999
pubmed: 28575679
Annu Rev Pathol. 2018 Jan 24;13:351-378
pubmed: 29125798
Oncogene. 2002 Nov 28;21(54):8293-301
pubmed: 12447692
Dev Cell. 2006 Jun;10(6):759-70
pubmed: 16740478
J Cell Mol Med. 2009 Jul;13(7):1371-80
pubmed: 18466352
Mol Cancer Ther. 2015 May;14(5):1224-35
pubmed: 25724664
Gastroenterology. 2015 Jun;148(7):1294-310
pubmed: 25747274
J Hepatol. 2008 May;48(5):829-34
pubmed: 18321606
Gastroenterology. 2014 Sep;147(3):690-701
pubmed: 24837480
Hepatology. 2016 Nov;64(5):1587-1605
pubmed: 27097116
Proc Natl Acad Sci U S A. 2017 Nov 7;114(45):11818-11825
pubmed: 29078414
Oncogene. 2007 Feb 1;26(5):774-80
pubmed: 16964294
Hepatology. 2014 Sep;60(3):964-76
pubmed: 24700412
Sci Signal. 2012 Mar 27;5(217):ra24
pubmed: 22457330
Nature. 2010 Dec 23;468(7327):1100-4
pubmed: 21179166
Am J Pathol. 2014 Dec;184(12):3284-98
pubmed: 25300578
J Biol Chem. 2016 Dec 16;291(51):26241-26251
pubmed: 27738108
Gastroenterology. 2008 Dec;135(6):1972-83, 1983.e1-11
pubmed: 18929564
Hepatology. 2014 Jun;59(6):2344-57
pubmed: 24214913
Hepatology. 2017 May;65(5):1581-1599
pubmed: 27981621
Nat Rev Cancer. 2018 Jan;18(1):51-63
pubmed: 29192214
Genes Dev. 2004 Aug 15;18(16):1926-45
pubmed: 15314020
JAMA. 2014 Jul 2;312(1):57-67
pubmed: 25058218
Hepatology. 2009 Mar;49(3):821-31
pubmed: 19101982
Science. 2015 Jan 9;347(6218):194-8
pubmed: 25567907
Cell. 2012 Jun 8;149(6):1192-205
pubmed: 22682243
Nat Rev Clin Oncol. 2014 Sep;11(9):506-7
pubmed: 25091613
Proteomics. 2009 Aug;9(15):3889-900
pubmed: 19639598
Cell. 2017 Apr 6;169(2):361-371
pubmed: 28388417
Cell Commun Signal. 2013 Mar 26;11(1):21
pubmed: 23531205
F1000Res. 2016 Aug 25;5:
pubmed: 27635236
Nat Rev Cancer. 2016 Nov;16(11):749
pubmed: 28704361
Hepatology. 2006 Mar;43(3):515-24
pubmed: 16496320
Gastroenterology. 2006 Nov;131(5):1561-72
pubmed: 17101329
Cancer Res. 2009 Jan 1;69(1):253-61
pubmed: 19118010
PLoS One. 2016 Apr 21;11(4):e0152695
pubmed: 27100093
Hepatology. 2006 Apr;43(4):817-25
pubmed: 16557553
Nature. 2015 Aug 13;524(7564):180-5
pubmed: 26245375
Hepatol Commun. 2018 Jun 21;2(7):845-860
pubmed: 30027142
Hepatology. 2016 Dec;64(6):2047-2061
pubmed: 27177928
Development. 2018 Jun 8;145(11):
pubmed: 29884654
Protein Sci. 1995 Nov;4(11):2358-65
pubmed: 8563633