Alteration of ribosome function upon 5-fluorouracil treatment favors cancer cell drug-tolerance.
Antimetabolites, Antineoplastic
/ pharmacology
Cell Line, Tumor
Cell Survival
/ drug effects
Colorectal Neoplasms
/ drug therapy
DNA Replication
DNA, Neoplasm
/ genetics
Drug Resistance, Neoplasm
/ genetics
Drug Tolerance
/ genetics
Fluorouracil
/ pharmacology
HCT116 Cells
Halogenation
Humans
Protein Biosynthesis
/ drug effects
RNA, Messenger
/ genetics
RNA, Ribosomal
/ genetics
Receptor, IGF Type 1
/ agonists
Ribosomes
/ drug effects
Xenograft Model Antitumor Assays
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
10 01 2022
10 01 2022
Historique:
received:
25
05
2020
accepted:
10
12
2021
entrez:
11
1
2022
pubmed:
12
1
2022
medline:
11
2
2022
Statut:
epublish
Résumé
Mechanisms of drug-tolerance remain poorly understood and have been linked to genomic but also to non-genomic processes. 5-fluorouracil (5-FU), the most widely used chemotherapy in oncology is associated with resistance. While prescribed as an inhibitor of DNA replication, 5-FU alters all RNA pathways. Here, we show that 5-FU treatment leads to the production of fluorinated ribosomes exhibiting altered translational activities. 5-FU is incorporated into ribosomal RNAs of mature ribosomes in cancer cell lines, colorectal xenografts, and human tumors. Fluorinated ribosomes appear to be functional, yet, they display a selective translational activity towards mRNAs depending on the nature of their 5'-untranslated region. As a result, we find that sustained translation of IGF-1R mRNA, which encodes one of the most potent cell survival effectors, promotes the survival of 5-FU-treated colorectal cancer cells. Altogether, our results demonstrate that "man-made" fluorinated ribosomes favor the drug-tolerant cellular phenotype by promoting translation of survival genes.
Identifiants
pubmed: 35013311
doi: 10.1038/s41467-021-27847-8
pii: 10.1038/s41467-021-27847-8
pmc: PMC8748862
doi:
Substances chimiques
Antimetabolites, Antineoplastic
0
DNA, Neoplasm
0
RNA, Messenger
0
RNA, Ribosomal
0
Receptor, IGF Type 1
EC 2.7.10.1
Fluorouracil
U3P01618RT
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
173Informations de copyright
© 2022. The Author(s).
Références
Nat Protoc. 2009;4(8):1184-91
pubmed: 19617889
Cancer Cell. 2013 Jun 10;23(6):811-25
pubmed: 23764003
Nucleic Acids Res. 2010 May;38(9):e104
pubmed: 20123731
Nat Commun. 2015 Jul 08;6:7646
pubmed: 26155016
Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):1795-9
pubmed: 9050858
Cancer Cell. 2013 Sep 9;24(3):318-30
pubmed: 24029231
BMC Genomics. 2006 Apr 03;7:68
pubmed: 16584549
Nucleic Acids Res. 2016 Jun 2;44(10):4978-87
pubmed: 27079977
Nat Rev Cancer. 2018 Apr;18(4):255-263
pubmed: 29376520
Nucleic Acids Res. 2011 Oct;39(19):8430-44
pubmed: 21745813
Bioinformatics. 2015 Jan 15;31(2):166-9
pubmed: 25260700
Mol Cell. 2011 Nov 18;44(4):660-6
pubmed: 22099312
FASEB J. 2015 Aug;29(8):3472-82
pubmed: 25934701
Br J Cancer. 2015 May 26;112(11):1725-32
pubmed: 25965164
J Biol Chem. 2001 Feb 23;276(8):5668-75
pubmed: 11063741
Nature. 2015 Apr 30;520(7549):640-5
pubmed: 25901680
World J Gastroenterol. 2006 Sep 21;12(35):5635-43
pubmed: 17007015
Nat Protoc. 2009;4(1):44-57
pubmed: 19131956
J Clin Oncol. 1991 Nov;9(11):2027-35
pubmed: 1941062
Cell. 2010 Apr 2;141(1):69-80
pubmed: 20371346
Trends Pharmacol Sci. 2019 Feb;40(2):128-141
pubmed: 30612715
PLoS One. 2013 Jun 21;8(6):e67313
pubmed: 23805307
Br J Cancer. 2005 Jun 20;92(12):2097-101
pubmed: 15956962
Trends Biochem Sci. 2002 Jul;27(7):344-51
pubmed: 12114023
J Pharm Anal. 2021 Feb;11(1):77-87
pubmed: 33717614
Nat Rev Cancer. 2018 Jan;18(1):51-63
pubmed: 29192214
Genome Biol. 2014;15(12):550
pubmed: 25516281
Cell. 2020 Nov 12;183(4):860-874
pubmed: 33186528
J Cell Physiol. 2008 Oct;217(1):172-83
pubmed: 18452152
Cell. 2014 Nov 20;159(5):1086-1095
pubmed: 25416947
Mol Cell Biol. 2013 Mar;33(5):1016-26
pubmed: 23275440
Cancer Cell. 2004 Mar;5(3):231-9
pubmed: 15050915
Oncotarget. 2017 Jul 11;8(28):46219-46233
pubmed: 28515355
Proc Natl Acad Sci U S A. 2013 Jan 2;110(1):324-9
pubmed: 23169626
J Biol Chem. 2010 Apr 16;285(16):12416-25
pubmed: 20159984
Br J Cancer. 1990 Mar;61(3):415-9
pubmed: 2328208
Nat Struct Mol Biol. 2017 Sep 7;24(9):689-699
pubmed: 28880863
Annu Rev Pathol. 2016 May 23;11:47-76
pubmed: 27193450
Nat Rev Cancer. 2020 Dec;20(12):743-756
pubmed: 33033407
Science. 2016 Jan 15;351(6270):
pubmed: 26816383
Nature. 2017 Nov 23;551(7681):472-477
pubmed: 29143818
Nat Rev Cancer. 2016 Apr 26;16(5):288-304
pubmed: 27112207
Biochem J. 2015 May 1;467(3):387-98
pubmed: 25628018
Cancer Cell. 2014 Jan 13;25(1):77-90
pubmed: 24434211
Nat Struct Mol Biol. 2015 Apr;22(4):342-344
pubmed: 25775268
Cold Spring Harb Perspect Biol. 2019 Jul 1;11(7):
pubmed: 29959193
Nat Rev Cancer. 2003 May;3(5):330-8
pubmed: 12724731
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Biochem Pharmacol. 2019 Jan;159:74-81
pubmed: 30468711
Nat Med. 2014 Sep;20(9):1027-34
pubmed: 25173427
Cancer Discov. 2016 Jan;6(1):59-70
pubmed: 26490423
Cell. 2018 Aug 9;174(4):843-855.e19
pubmed: 30017245
Proc Natl Acad Sci U S A. 2017 Dec 5;114(49):12934-12939
pubmed: 29158377
PLoS One. 2009 Sep 25;4(9):e7147
pubmed: 19779612
Proc Natl Acad Sci U S A. 2017 Dec 26;114(52):13679-13684
pubmed: 29229836
Biochem Pharmacol. 1987 Oct 1;36(19):3243-8
pubmed: 2444230
Biochem Pharmacol. 2019 Apr;162:169-176
pubmed: 30414937
Nucleic Acids Res. 2016 Jul 8;44(W1):W83-9
pubmed: 27098042
Pharmacol Res. 2004 Aug;50(2):173-9
pubmed: 15177306
J Cell Biochem. 2010 May 15;110(2):531-44
pubmed: 20432247
Nat Rev Mol Cell Biol. 2012 May 23;13(6):355-69
pubmed: 22617470
Nat Methods. 2012 Jul;9(7):671-5
pubmed: 22930834
Ann Oncol. 2016 Sep;27 Suppl 3:iii42-iii50
pubmed: 27573756