Creatine riboside is a cancer cell-derived metabolite associated with arginine auxotrophy.
Cancer
Lung cancer
Oncology
Journal
The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877
Informations de publication
Date de publication:
15 07 2022
15 07 2022
Historique:
received:
08
12
2021
accepted:
25
05
2022
entrez:
15
7
2022
pubmed:
16
7
2022
medline:
19
7
2022
Statut:
ppublish
Résumé
The metabolic dependencies of cancer cells have substantial potential to be exploited to improve the diagnosis and treatment of cancer. Creatine riboside (CR) is identified as a urinary metabolite associated with risk and prognosis in lung and liver cancer. However, the source of high CR levels in patients with cancer as well as their implications for the treatment of these aggressive cancers remain unclear. By integrating multiomics data on lung and liver cancer, we have shown that CR is a cancer cell-derived metabolite. Global metabolomics and gene expression analysis of human tumors and matched liquid biopsies, together with functional studies, revealed that dysregulation of the mitochondrial urea cycle and a nucleotide imbalance were associated with high CR levels and indicators of a poor prognosis. This metabolic phenotype was associated with reduced immune infiltration and supported rapid cancer cell proliferation that drove aggressive tumor growth. CRhi cancer cells were auxotrophic for arginine, revealing a metabolic vulnerability that may be exploited therapeutically. This highlights the potential of CR not only as a poor-prognosis biomarker but also as a companion biomarker to inform the administration of arginine-targeted therapies in precision medicine strategies to improve survival for patients with cancer.
Identifiants
pubmed: 35838048
pii: 157410
doi: 10.1172/JCI157410
pmc: PMC9282934
doi:
pii:
Substances chimiques
2-(2-(3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl)-1-methylcarbamimidamido)acetic acid
0
Ribonucleosides
0
Arginine
94ZLA3W45F
Creatine
MU72812GK0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Références
J Pharm Biomed Anal. 2020 Nov 30;191:113596
pubmed: 32937240
Cancer Discov. 2020 Dec;10(12):1797-1807
pubmed: 33139243
Nat Metab. 2020 Jan;2(1):62-80
pubmed: 32694686
J Thorac Oncol. 2016 Jun;11(6):789-800
pubmed: 26845192
Nat Commun. 2019 Jul 5;10(1):2978
pubmed: 31278276
J Thorac Oncol. 2012 Apr;7(4):723-30
pubmed: 22425921
Int J Cancer. 1995 Apr 10;61(2):199-205
pubmed: 7705948
Nat Biotechnol. 2019 Jul;37(7):773-782
pubmed: 31061481
Mol Cell. 2019 Dec 5;76(5):838-851.e5
pubmed: 31564558
N Engl J Med. 2011 Aug 4;365(5):395-409
pubmed: 21714641
Int J Cancer. 2010 Jun 15;126(12):2762-72
pubmed: 20104527
Bioinformatics. 2012 Mar 15;28(6):882-3
pubmed: 22257669
Nat Med. 2021 Aug;27(8):1345-1356
pubmed: 34385702
Cell. 2011 Mar 4;144(5):646-74
pubmed: 21376230
Mol Med Rep. 2015 Dec;12(6):7915-26
pubmed: 26499888
Nucleic Acids Res. 2012 May;40(10):4288-97
pubmed: 22287627
J Biol Chem. 1987 Oct 5;262(28):13520-6
pubmed: 2443493
J Vis Exp. 2012 Jan 21;(59):
pubmed: 22297617
Genome Res. 2018 Nov;28(11):1747-1756
pubmed: 30341162
Cancer Epidemiol Biomarkers Prev. 2016 Jun;25(6):978-86
pubmed: 27013655
Nature. 2017 Jun 1;546(7656):168-172
pubmed: 28538732
Mol Syst Biol. 2011 Aug 16;7:523
pubmed: 21847114
Cell. 2017 Feb 9;168(4):657-669
pubmed: 28187287
Nature. 2014 Jul 31;511(7511):543-50
pubmed: 25079552
Cell. 2018 Sep 6;174(6):1559-1570.e22
pubmed: 30100185
Cell Rep. 2016 Oct 11;17(3):837-848
pubmed: 27732858
Cancer Cell. 2012 Mar 20;21(3):297-308
pubmed: 22439925
Lancet Oncol. 2016 May;17(5):590-9
pubmed: 27009070
Cell. 2017 Jun 15;169(7):1327-1341.e23
pubmed: 28622513
Nat Methods. 2015 May;12(5):453-7
pubmed: 25822800
Cancer Med. 2021 Oct;10(19):6642-6652
pubmed: 34382365
Cancer Res. 1993 Mar 1;53(5):985-91
pubmed: 8094998
Curr Opin Biotechnol. 2015 Aug;34:189-201
pubmed: 25731751
Lancet Oncol. 2020 Dec;21(12):1589-1601
pubmed: 33125909
Cell. 2015 Jul 30;162(3):540-51
pubmed: 26232224
Nucleic Acids Res. 2015 Apr 20;43(7):e47
pubmed: 25605792
Cancer Epidemiol Biomarkers Prev. 2019 Oct;28(10):1704-1711
pubmed: 31358519
Nat Genet. 2016 Jun;48(6):607-16
pubmed: 27158780
Cancer Cell. 2010 Jan 19;17(1):89-97
pubmed: 20129250
Cancer Res. 2014 Jun 15;74(12):3259-70
pubmed: 24736543
Nat Med. 2019 Mar;25(3):517-525
pubmed: 30664780
Nature. 2015 Nov 19;527(7578):379-383
pubmed: 26560030
JAMA Netw Open. 2019 Mar 1;2(3):e190204
pubmed: 30821827
Am J Pathol. 2011 Feb;178(2):652-61
pubmed: 21281797
Science. 2020 Apr 10;368(6487):
pubmed: 32273439
Blood. 2015 Apr 9;125(15):2386-96
pubmed: 25710880
Cell. 2017 Apr 06;169(2):258-272.e17
pubmed: 28388410
Cancer Cell. 2017 Jul 10;32(1):57-70.e3
pubmed: 28648284
Sci Rep. 2017 Apr 05;7:45913
pubmed: 28378759
Protein Cell. 2014;5(8):592-602
pubmed: 25015087
Nat Commun. 2021 Mar 5;12(1):1455
pubmed: 33674593
Cell Rep. 2013 May 30;3(5):1440-8
pubmed: 23643539
Histopathology. 2009 Jan;54(1):43-54
pubmed: 19187179
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Cancer Discov. 2012 Oct;2(10):881-98
pubmed: 23009760
Cancer Res. 2007 Jan 1;67(1):309-17
pubmed: 17210712
J Biol Chem. 2003 Jul 11;278(28):26202-7
pubmed: 12711607
Cell. 2018 Apr 5;173(2):400-416.e11
pubmed: 29625055
BMC Med. 2013 Mar 04;11:60
pubmed: 23497222
Cell Metab. 2018 Apr 3;27(4):935-943.e4
pubmed: 29526543
Genome Med. 2018 Apr 25;10(1):33
pubmed: 29695279
Nat Rev Cancer. 2018 Oct;18(10):634-645
pubmed: 30194362
Mol Genet Metab. 2010;100 Suppl 1:S49-52
pubmed: 20304692
Oncogene. 2020 Jan;39(1):164-175
pubmed: 31462712
BMC Cancer. 2010 May 20;10:220
pubmed: 20487543
Lung Cancer. 2019 Mar;129:16-21
pubmed: 30797486
Nat Commun. 2018 Dec 14;9(1):5330
pubmed: 30552315
Invest New Drugs. 2021 Oct;39(5):1375-1382
pubmed: 33856599
J Natl Cancer Inst. 2017 Mar 1;109(3):1-9
pubmed: 28376202
Clin Cancer Res. 2017 Sep 1;23(17):5302-5310
pubmed: 28450405
Nature. 2012 Sep 27;489(7417):519-25
pubmed: 22960745
J Clin Invest. 2004 Nov;114(9):1248-59
pubmed: 15520857
Nucleic Acids Res. 2015 Feb 27;43(4):2466-85
pubmed: 25628363
Cell. 2015 Jul 30;162(3):552-63
pubmed: 26232225
Diabetes. 1991 Oct;40(10):1259-66
pubmed: 1657665
J Clin Invest. 2015 Feb;125(2):687-98
pubmed: 25607840
Mol Cancer. 2009 Jun 26;8:41
pubmed: 19558692
ACS Chem Biol. 2017 Apr 21;12(4):905-911
pubmed: 28229591
Carcinogenesis. 2016 Aug;37(8):787-798
pubmed: 27207668
Biomolecules. 2020 Apr 08;10(4):
pubmed: 32276417
Commun Biol. 2018 Oct 26;1:178
pubmed: 30393775