Immune-regulated IDO1-dependent tryptophan metabolism is source of one-carbon units for pancreatic cancer and stellate cells.
Allografts
Animals
Antineoplastic Agents
/ pharmacology
Carbon
/ immunology
Carcinoma, Pancreatic Ductal
/ drug therapy
Cell Line, Tumor
Formates
/ immunology
Gene Expression Regulation, Neoplastic
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase
/ genetics
Interferon-gamma
/ genetics
Metabolic Networks and Pathways
/ drug effects
Mice
Mice, Inbred C57BL
Mice, Nude
Oximes
/ pharmacology
Pancreatic Neoplasms
/ drug therapy
Pancreatic Stellate Cells
/ drug effects
Proto-Oncogene Proteins p21(ras)
/ genetics
Serine
/ immunology
Signal Transduction
Sulfonamides
/ pharmacology
Tryptophan
/ immunology
Tumor Escape
/ drug effects
Tumor Suppressor Protein p53
/ genetics
IDO1
IFNγ
PDAC
cancer immunology
cancer metabolism
epacadostat
formate
immunometabolism
immunotherapy
one-carbon metabolism
pancreas
serine
stellate cells
tryptophan
tumor microenvironment
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
03 06 2021
03 06 2021
Historique:
received:
13
01
2020
revised:
15
12
2020
accepted:
12
03
2021
pubmed:
9
4
2021
medline:
23
6
2021
entrez:
8
4
2021
Statut:
ppublish
Résumé
Cancer cells adapt their metabolism to support elevated energetic and anabolic demands of proliferation. Folate-dependent one-carbon metabolism is a critical metabolic process underpinning cellular proliferation supplying carbons for the synthesis of nucleotides incorporated into DNA and RNA. Recent research has focused on the nutrients that supply one-carbons to the folate cycle, particularly serine. Tryptophan is a theoretical source of one-carbon units through metabolism by IDO1, an enzyme intensively investigated in the context of tumor immune evasion. Using in vitro and in vivo pancreatic cancer models, we show that IDO1 expression is highly context dependent, influenced by attachment-independent growth and the canonical activator IFNγ. In IDO1-expressing cancer cells, tryptophan is a bona fide one-carbon donor for purine nucleotide synthesis in vitro and in vivo. Furthermore, we show that cancer cells release tryptophan-derived formate, which can be used by pancreatic stellate cells to support purine nucleotide synthesis.
Identifiants
pubmed: 33831358
pii: S1097-2765(21)00214-8
doi: 10.1016/j.molcel.2021.03.019
pmc: PMC8189438
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
Formates
0
IDO1 protein, human
0
IDO1 protein, mouse
0
Indoleamine-Pyrrole 2,3,-Dioxygenase
0
Oximes
0
Sulfonamides
0
Trp53 protein, mouse
0
Tumor Suppressor Protein p53
0
formic acid
0YIW783RG1
Serine
452VLY9402
epacadostat
71596A9R13
Carbon
7440-44-0
Interferon-gamma
82115-62-6
Tryptophan
8DUH1N11BX
Hras protein, mouse
EC 3.6.5.2
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2290-2302.e7Subventions
Organisme : Cancer Research UK
ID : C53309/A19702
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A17196
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A29799
Pays : United Kingdom
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests O.D.K.M. contributed to CRUK Cancer Research Technology filing of UK patent application no. 1609441.9, relating to dietary modulation of amino acids, and is a co-founder, shareholder, and advisor of Faeth Therapeutics. The other authors declare no competing interests.
Références
Sci Adv. 2016 Oct 28;2(10):e1601273
pubmed: 27819051
Int J Mol Sci. 2017 Dec 28;19(1):
pubmed: 29283429
Cancer Cell. 2005 May;7(5):469-83
pubmed: 15894267
Nature. 2020 Oct;586(7831):790-795
pubmed: 32788725
Elife. 2019 Apr 16;8:
pubmed: 30990168
Nat Genet. 2011 Jul 31;43(9):869-74
pubmed: 21804546
Oncogene. 2008 Jun 26;27(28):3889-900
pubmed: 18317452
Cell Physiol Biochem. 2018;49(1):134-143
pubmed: 30134237
J Immunol. 2010 Sep 15;185(6):3190-8
pubmed: 20720200
Nature. 2017 Apr 19;544(7650):372-376
pubmed: 28425994
J Immunol. 2014 Sep 1;193(5):2574-86
pubmed: 25063873
Oncotarget. 2014 Feb 28;5(4):1038-51
pubmed: 24657910
J Immunol. 2009 May 15;182(10):5899-903
pubmed: 19414739
Immunol Rev. 2008 Apr;222:206-21
pubmed: 18364004
Nature. 2013 Jan 24;493(7433):542-6
pubmed: 23242140
Front Immunol. 2018 Jan 31;9:151
pubmed: 29445380
Cell Metab. 2019 Jun 4;29(6):1410-1421.e4
pubmed: 30905671
Nature. 2016 Aug 25;536(7617):479-83
pubmed: 27509858
Mol Cell Biol. 2003 Jun;23(11):4013-25
pubmed: 12748302
Cell. 2011 Mar 4;144(5):646-74
pubmed: 21376230
Trends Cell Biol. 2017 Sep;27(9):645-657
pubmed: 28601431
Immunity. 2005 May;22(5):633-42
pubmed: 15894280
Science. 2012 May 25;336(6084):1040-4
pubmed: 22628656
Nat Cell Biol. 2020 Jul;22(7):779-790
pubmed: 32451440
Science. 2018 May 11;360(6389):588
pubmed: 29748264
Nat Chem Biol. 2016 Jun;12(6):452-8
pubmed: 27110680
J Exp Med. 2003 Aug 4;198(3):433-42
pubmed: 12900519
Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):246-51
pubmed: 20018721
Nucleic Acids Res. 2016 Jan 4;44(D1):D560-6
pubmed: 26626150
Nature. 2015 Apr 16;520(7547):363-7
pubmed: 25855294
Blood. 2010 Apr 29;115(17):3520-30
pubmed: 20197554
Nature. 2018 Jul;559(7715):632-636
pubmed: 29995852
Nat Commun. 2018 Apr 10;9(1):1368
pubmed: 29636461
Biochem J. 2009 Jan 1;417(1):1-13
pubmed: 19061483
J Adv Res. 2020 Mar 29;24:139-148
pubmed: 32322419
Cancer Immunol Res. 2017 Aug;5(8):695-709
pubmed: 28765120
Br J Cancer. 2017 Jun 6;116(12):1499-1504
pubmed: 28472819
Nature. 2017 Aug 31;548(7669):549-554
pubmed: 28813411
Cell Metab. 2016 Jun 14;23(6):1140-1153
pubmed: 27211901
J Exp Med. 2002 Aug 19;196(4):447-57
pubmed: 12186837
Cell Metab. 2020 Feb 4;31(2):339-350.e4
pubmed: 31813821
Nature. 2011 Aug 18;476(7360):346-50
pubmed: 21760589
Oncoimmunology. 2016 Nov 15;5(12):e1240858
pubmed: 28123877
Cell Rep. 2014 May 22;7(4):1248-58
pubmed: 24813884
Cancer Discov. 2019 May;9(5):617-627
pubmed: 30837243