Nutlin-3a suppresses poly (ADP-ribose) polymerase 1 by mechanisms different from conventional PARP1 suppressors in a human breast cancer cell line.
PARP1
autoPARylation
breast cancer
nutlin-3a
proteasomal degradation
Journal
Oncotarget
ISSN: 1949-2553
Titre abrégé: Oncotarget
Pays: United States
ID NLM: 101532965
Informations de publication
Date de publication:
05 May 2020
05 May 2020
Historique:
received:
21
12
2019
accepted:
14
04
2020
entrez:
15
5
2020
pubmed:
15
5
2020
medline:
15
5
2020
Statut:
epublish
Résumé
Poly (ADP-ribose) polymerase 1 (PARP1) plays important roles in single strand DNA repair. PARP1 inhibitors enhance the effects of DNA damaging drugs in homologous recombination-deficient tumors including tumors with breast cancer susceptibility gene (BRCA1) mutation. Nutlin-3a, an analog of cis-imidazoline, inhibits degradation of murine double minute 2 (MDM2) and stabilizes p53. We previously reported that nutlin-3a induces PARP1 degradation in p53-dependent manner in mouse fibroblasts, suggesting nutlin-3a may be a PARP1 suppressor. Here, we investigated the effects of nutlin-3a on PARP1 in MCF-7, a human breast cancer cell line. Consistent with our previous results, nutlin-3a reduced PARP1 levels in dose- and time-dependent manners in MCF-7 cells, but this reduction was suppressed in p53 knockdown cells. RITA, a p53 stabilizer that binds to p53 itself, failed to reduce PARP1 protein levels. Moreover, transient MDM2 knockdown repressed nutlin-3a-mediated PARP1 reduction. The MG132 proteasome inhibitor, and knockdown of checkpoint with forkhead and ring finger domains (CHFR) and ring finger protein 146 (RNF146), E3 ubiquitin ligases targeting PARP1, suppressed nutlin-3a-induced PARP1 reduction. Short-term nutlin-3a treatment elevated the levels of PARylated PARP1, suggesting nutlin-3a promoted PARylation of PARP1, thereby inducing its proteasomal degradation. Furthermore, nutlin-3a-induced PARP1 degradation enhanced DNA-damaging effects of cisplatin in BRCA1 knockdown cells. Our study revealed that nutlin-3a is a PARP1 suppressor that induces PARP1 proteasomal degradation by binding to MDM2 and promoting autoPARylation of PARP1. Further analysis of the mechanisms in nutlin-3a-induced PARP1 degradation may lead to the development of novel PARP1 suppressors applicable for cancers with BRCA1 mutation.
Identifiants
pubmed: 32405340
doi: 10.18632/oncotarget.27581
pii: 27581
pmc: PMC7210013
doi:
Types de publication
Journal Article
Langues
eng
Pagination
1653-1665Déclaration de conflit d'intérêts
CONFLICTS OF INTEREST The authors declare no conflicts of interest.
Références
Biochem Biophys Res Commun. 2012 Nov 2;427(4):758-63
pubmed: 23041188
Acta Naturae. 2015 Jul-Sep;7(3):27-37
pubmed: 26483957
Nat Rev Clin Oncol. 2015 Jan;12(1):27-41
pubmed: 25286972
CA Cancer J Clin. 2011 Jan-Feb;61(1):31-49
pubmed: 21205831
J Biol Chem. 2015 Feb 6;290(6):3775-83
pubmed: 25477519
Cancer Res. 2002 Jan 1;62(1):219-25
pubmed: 11782381
N Engl J Med. 2017 Aug 10;377(6):523-533
pubmed: 28578601
Oncogene. 2016 Sep 1;35(35):4569-79
pubmed: 26898760
Clin Cancer Res. 2007 Mar 1;13(5):1383-8
pubmed: 17332279
Biochem Biophys Res Commun. 2011 Apr 15;407(3):557-61
pubmed: 21419099
J Proteome Res. 2012 Nov 2;11(11):5464-78
pubmed: 23039052
Biochem Biophys Res Commun. 2012 Apr 27;421(1):15-9
pubmed: 22465010
PLoS Genet. 2013 Jun;9(6):e1003531
pubmed: 23785295
Nat Rev Mol Cell Biol. 2012 Jun 20;13(7):411-24
pubmed: 22713970
Mol Cell. 2006 Jul 21;23(2):251-63
pubmed: 16857591
Nat Rev Mol Cell Biol. 2006 Jul;7(7):517-28
pubmed: 16829982
Mol Cell Oncol. 2015 Jun 10;3(2):e1053594
pubmed: 27308587
Cancer Res. 2012 Apr 1;72(7):1608-13
pubmed: 22287547
Nucleic Acids Res. 2009 Jun;37(11):3723-38
pubmed: 19372272
Mol Cell. 2010 Sep 10;39(5):736-49
pubmed: 20832725
Science. 2004 Feb 6;303(5659):844-8
pubmed: 14704432
Nat Med. 2004 Dec;10(12):1321-8
pubmed: 15558054
Clin Cancer Res. 2017 Jan 15;23(2):514-522
pubmed: 28034904
Nature. 2005 Apr 14;434(7035):917-21
pubmed: 15829967
Mutat Res. 2001 Jun 2;477(1-2):97-110
pubmed: 11376691
EMBO Rep. 2006 Feb;7(2):219-24
pubmed: 16322760
Science. 2009 Sep 4;325(5945):1240-3
pubmed: 19661379
Cell. 2018 Jan 25;172(3):439-453.e14
pubmed: 29290468
Annu Rev Pharmacol Toxicol. 2009;49:223-41
pubmed: 18834305
Mol Cell Biol. 2018 Jun 14;38(13):
pubmed: 29661921
Genes Dev. 2017 Feb 1;31(3):318-332
pubmed: 28242626
J Virol. 2012 Aug;86(15):8259-68
pubmed: 22623791
Mol Med. 2011;17(7-8):854-62
pubmed: 21424107
Carcinogenesis. 2014 Oct;35(10):2273-82
pubmed: 25085902
Nature. 2005 Apr 14;434(7035):913-7
pubmed: 15829966
Nat Neurosci. 2013 Oct;16(10):1392-400
pubmed: 23974709
J Biol Chem. 2012 Apr 13;287(16):12975-84
pubmed: 22337872
J Biol Chem. 1992 Jan 25;267(3):1569-75
pubmed: 1530940
Cancer Cell. 2018 Jun 11;33(6):1078-1093.e12
pubmed: 29894693
Nature. 2008 Jan 3;451(7174):81-5
pubmed: 18172500
Nat Med. 2016 Feb;22(2):194-201
pubmed: 26779812
J Biol Chem. 2002 Jun 21;277(25):23028-36
pubmed: 11948190
J Cell Sci. 2005 Jan 1;118(Pt 1):211-22
pubmed: 15615785
Br J Cancer. 2016 Nov 8;115(10):1157-1173
pubmed: 27736844
Genes Dev. 2012 Feb 1;26(3):235-40
pubmed: 22267412
Science. 2012 May 11;336(6082):728-32
pubmed: 22582261
Lancet Oncol. 2014 Jul;15(8):852-61
pubmed: 24882434
Trends Biochem Sci. 2001 May;26(5):273-5
pubmed: 11343911
Trends Biochem Sci. 2012 Sep;37(9):381-90
pubmed: 22766145
N Engl J Med. 2015 Oct 29;373(18):1697-708
pubmed: 26510020
Proc Natl Acad Sci U S A. 2011 Aug 23;108(34):14103-8
pubmed: 21825151
Mol Cell. 2016 May 5;62(3):432-442
pubmed: 27067600
Mol Cell. 2013 Jan 10;49(1):7-17
pubmed: 23219533