MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis.
Journal
Nature cancer
ISSN: 2662-1347
Titre abrégé: Nat Cancer
Pays: England
ID NLM: 101761119
Informations de publication
Date de publication:
04 2022
04 2022
Historique:
received:
13
08
2021
accepted:
28
02
2022
entrez:
28
4
2022
pubmed:
29
4
2022
medline:
3
5
2022
Statut:
ppublish
Résumé
Aberrant expression of MYC transcription factor family members predicts poor clinical outcome in many human cancers. Oncogenic MYC profoundly alters metabolism and mediates an antioxidant response to maintain redox balance. Here we show that MYCN induces massive lipid peroxidation on depletion of cysteine, the rate-limiting amino acid for glutathione (GSH) biosynthesis, and sensitizes cells to ferroptosis, an oxidative, non-apoptotic and iron-dependent type of cell death. The high cysteine demand of MYCN-amplified childhood neuroblastoma is met by uptake and transsulfuration. When uptake is limited, cysteine usage for protein synthesis is maintained at the expense of GSH triggering ferroptosis and potentially contributing to spontaneous tumor regression in low-risk neuroblastomas. Pharmacological inhibition of both cystine uptake and transsulfuration combined with GPX4 inactivation resulted in tumor remission in an orthotopic MYCN-amplified neuroblastoma model. These findings provide a proof of concept of combining multiple ferroptosis targets as a promising therapeutic strategy for aggressive MYCN-amplified tumors.
Identifiants
pubmed: 35484422
doi: 10.1038/s43018-022-00355-4
pii: 10.1038/s43018-022-00355-4
pmc: PMC9050595
doi:
Substances chimiques
MYCN protein, human
0
N-Myc Proto-Oncogene Protein
0
Glutathione
GAN16C9B8O
Cysteine
K848JZ4886
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
471-485Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2022. The Author(s).
Références
Cell Chem Biol. 2020 Apr 16;27(4):365-375
pubmed: 32294465
Cell Death Differ. 2016 Feb;23(2):270-8
pubmed: 26184909
Nat Chem Biol. 2016 Feb;12(2):109-16
pubmed: 26656090
Proc Natl Acad Sci U S A. 2013 Jun 18;110(25):10258-63
pubmed: 23733953
Cell. 2012 Sep 28;151(1):56-67
pubmed: 23021215
Nat Methods. 2015 Oct;12(10):963-965
pubmed: 26280331
Proc Natl Acad Sci U S A. 2012 Jan 24;109(4):1092-7
pubmed: 22228304
Nucleic Acids Res. 2014 Jul;42(Web Server issue):W187-91
pubmed: 24799436
Nature. 2015 Oct 29;526(7575):700-4
pubmed: 26466568
Cancer Cell. 2012 Nov 13;22(5):631-44
pubmed: 23153536
Genome Biol. 2015 Jun 25;16:133
pubmed: 26109056
F1000Res. 2016 Jun 15;5:1384
pubmed: 30101006
FEBS J. 2022 Jan;289(2):374-385
pubmed: 33773039
Cell Metab. 2019 Nov 5;30(5):865-876.e5
pubmed: 31607565
Mol Cell Biol. 2006 Mar;26(6):2373-86
pubmed: 16508012
Cancer Res. 2016 Sep 15;76(18):5523-37
pubmed: 27635046
Commun Biol. 2018 Nov 28;1:210
pubmed: 30511023
Cell Death Differ. 2011 Jun;18(6):974-84
pubmed: 21233845
Nature. 2020 Sep;585(7823):113-118
pubmed: 32814895
Nat Protoc. 2013 Mar;8(3):539-54
pubmed: 23429716
Nat Genet. 2017 Aug;49(8):1261-1266
pubmed: 28650485
Cancer Discov. 2015 Oct;5(10):1024-39
pubmed: 26382145
Cell Metab. 2020 Dec 1;32(6):920-937
pubmed: 33217331
Genome Biol. 2008 Oct 13;9(10):R150
pubmed: 18851746
Mol Microbiol. 2015 Jun;96(6):1272-82
pubmed: 25807888
Cancer Cell. 2008 Dec 9;14(6):447-57
pubmed: 19061836
Clin Chem. 1997 Dec;43(12):2397-402
pubmed: 9439460
Oncogene. 1996 Aug 15;13(4):803-12
pubmed: 8761302
Cell Syst. 2017 Sep 27;5(3):237-250.e8
pubmed: 28843484
Nucleic Acids Res. 2009 Oct;37(18):e119
pubmed: 19589807
Cell. 2014 Jan 16;156(1-2):317-331
pubmed: 24439385
J Biol Chem. 2015 Jun 19;290(25):15878-15891
pubmed: 25931127
Nat Rev Mol Cell Biol. 2021 Apr;22(4):266-282
pubmed: 33495651
Nat Commun. 2021 Feb 24;12(1):1269
pubmed: 33627664
Mol Cell. 2015 Jul 16;59(2):298-308
pubmed: 26166707
Cancer Res. 2021 Apr 1;81(7):1896-1908
pubmed: 33483374
Cell Chem Biol. 2019 May 16;26(5):623-633.e9
pubmed: 30799221
Bioinformatics. 2010 Jan 1;26(1):139-40
pubmed: 19910308
Proc Natl Acad Sci U S A. 2008 Dec 2;105(48):18782-7
pubmed: 19033189
Elife. 2014 May 20;3:e02523
pubmed: 24844246
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Front Oncol. 2020 May 07;10:723
pubmed: 32457843
Cancer Res. 2010 May 1;70(9):3791-802
pubmed: 20424123
Cancer Lett. 2005 Oct 18;228(1-2):133-41
pubmed: 15927359
Cell Rep. 2020 Mar 10;30(10):3411-3423.e7
pubmed: 32160546
Cell. 2017 Jul 27;170(3):577-592.e10
pubmed: 28753431
Nat Cancer. 2021 Jan;2(1):114-128
pubmed: 35121888
Mol Cell. 2019 Jan 17;73(2):354-363.e3
pubmed: 30581146
Amino Acids. 2012 Jan;42(1):199-205
pubmed: 21369939
Cell Death Dis. 2021 May 19;12(6):511
pubmed: 34011924
J Exp Bot. 2004 Aug;55(404):1785-98
pubmed: 15258168
Nat Protoc. 2006;1(3):1112-6
pubmed: 17406391
Free Radic Biol Med. 2012 Jul 15;53(2):366-74
pubmed: 22579918
Cell. 2012 May 25;149(5):1060-72
pubmed: 22632970
Adv Exp Med Biol. 2021;1301:1-5
pubmed: 34370284
N Engl J Med. 2010 Jun 10;362(23):2202-11
pubmed: 20558371
In Vivo. 2002 Mar-Apr;16(2):77-85
pubmed: 12073775