HMGA2 as a functional antagonist of PARP1 inhibitors in tumor cells.
AT-Hook Motifs
Amino Acid Sequence
Animals
Apoptosis
/ drug effects
Cell Line, Tumor
Cell Respiration
/ drug effects
Cell Survival
/ drug effects
Cytoprotection
/ drug effects
DNA Damage
Drug Resistance, Neoplasm
/ drug effects
HMGA2 Protein
/ chemistry
Humans
Methyl Methanesulfonate
Mice
Mitochondria
/ metabolism
Nicotinamide Phosphoribosyltransferase
/ metabolism
Phthalazines
/ pharmacology
Piperazines
/ pharmacology
Poly Adenosine Diphosphate Ribose
/ metabolism
Poly(ADP-ribose) Polymerase Inhibitors
/ pharmacology
Poly(ADP-ribose) Polymerases
/ metabolism
Protein Binding
Triple Negative Breast Neoplasms
/ pathology
HMGA2
PARP1
PARP1 trapping
PARylation
olaparib
Journal
Molecular oncology
ISSN: 1878-0261
Titre abrégé: Mol Oncol
Pays: United States
ID NLM: 101308230
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
22
05
2018
revised:
19
09
2018
accepted:
20
09
2018
pubmed:
6
10
2018
medline:
18
12
2019
entrez:
6
10
2018
Statut:
ppublish
Résumé
Poly(ADP-ribose) polymerase 1 inhibitors alone or in combination with DNA damaging agents are promising clinical drugs in the treatment of cancer. However, there is a need to understand the molecular mechanisms of resistance to PARP1 inhibitors. Expression of HMGA2 in cancer is associated with poor prognosis for patients. Here, we investigated the novel relationship between HMGA2 and PARP1 in DNA damage-induced PARP1 activity. We used human triple-negative breast cancer and fibrosarcoma cell lines to demonstrate that HMGA2 colocalizes and interacts with PARP1. High cellular HMGA2 levels correlated with increased DNA damage-induced PARP1 activity, which was dependent on functional DNA-binding AT-hook domains of HMGA2. HMGA2 inhibited PARP1 trapping to DNA and counteracted the cytotoxic effect of PARP inhibitors. Consequently, HMGA2 decreased caspase 3/7 induction and increased cell survival upon treatment with the alkylating methyl methanesulfonate alone or in combination with the PARP inhibitor AZD2281 (olaparib). HMGA2 increased mitochondrial oxygen consumption rate and spare respiratory capacity and increased NAMPT levels, suggesting metabolic support for enhanced PARP1 activity upon DNA damage. Our data showed that expression of HMGA2 in cancer cells reduces sensitivity to PARP inhibitors and suggests that targeting HMGA2 in combination with PARP inhibition may be a promising new therapeutic approach.
Identifiants
pubmed: 30289618
doi: 10.1002/1878-0261.12390
pmc: PMC6360374
doi:
Substances chimiques
HMGA2 Protein
0
Phthalazines
0
Piperazines
0
Poly(ADP-ribose) Polymerase Inhibitors
0
Poly Adenosine Diphosphate Ribose
26656-46-2
Methyl Methanesulfonate
AT5C31J09G
Nicotinamide Phosphoribosyltransferase
EC 2.4.2.12
Poly(ADP-ribose) Polymerases
EC 2.4.2.30
olaparib
WOH1JD9AR8
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
153-170Informations de copyright
© 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.
Références
J Biol Chem. 2012 Aug 10;287(33):27648-58
pubmed: 22736760
J Biol Chem. 1990 May 25;265(15):8573-82
pubmed: 1692833
Nucleic Acids Res. 2009 Jun;37(11):3723-38
pubmed: 19372272
Cancer Res. 2013 Jul 15;73(14):4289-99
pubmed: 23722545
Nature. 2005 Apr 14;434(7035):917-21
pubmed: 15829967
J Biol Chem. 2011 Mar 25;286(12):10690-701
pubmed: 21233213
Genes Chromosomes Cancer. 1999 Aug;25(4):316-22
pubmed: 10398424
J Biol Chem. 2016 Jan 22;291(4):1789-802
pubmed: 26559976
Proc Natl Acad Sci U S A. 2010 Dec 21;107(51):22090-5
pubmed: 21127267
EMBO Mol Med. 2013 Feb;5(2):264-79
pubmed: 23307470
FEBS J. 2005 Apr;272(8):2012-21
pubmed: 15819892
Genes Dev. 2005 Sep 1;19(17):1951-67
pubmed: 16140981
Front Pharmacol. 2013 Feb 27;4:18
pubmed: 23450678
Cell. 2008 Dec 12;135(6):1013-6
pubmed: 19070572
Mol Cell Biol. 2004 May;24(10):4321-8
pubmed: 15121851
Genes Dev. 1997 Sep 15;11(18):2347-58
pubmed: 9308963
Am J Pathol. 1996 Sep;149(3):775-9
pubmed: 8780382
Cell Rep. 2014 Feb 27;6(4):684-97
pubmed: 24508460
Biochem Pharmacol. 2012 Jul 15;84(2):137-46
pubmed: 22469522
Mol Cancer Res. 2012 Mar;10(3):360-8
pubmed: 22246237
Cell Rep. 2014 Sep 25;8(6):1819-1831
pubmed: 25220464
Mutat Res. 1989 Sep;218(2):67-74
pubmed: 2770765
Oncogene. 2014 Jul 3;33(27):3528-37
pubmed: 23975428
Oncotarget. 2016 Mar 15;7(11):12761-82
pubmed: 26799419
Cell. 2007 Dec 14;131(6):1109-23
pubmed: 18083101
Cell Stem Cell. 2008 Jan 10;2(1):8-9
pubmed: 18371414
Mol Cancer Ther. 2014 Feb;13(2):433-43
pubmed: 24356813
Stem Cell Rev Rep. 2009 Sep;5(3):224-30
pubmed: 19551524
Nat Methods. 2006 Dec;3(12):995-1000
pubmed: 17072308
Genes Dev. 2012 Mar 1;26(5):417-32
pubmed: 22391446
Nat Rev Endocrinol. 2015 Sep;11(9):535-46
pubmed: 26215259
Biochim Biophys Acta Rev Cancer. 2018 Apr;1869(2):216-229
pubmed: 29518471
Mol Cell. 2013 Oct 24;52(2):272-85
pubmed: 24055347
Nucleic Acids Res. 2009 Jul;37(13):4371-84
pubmed: 19465398
J Neurochem. 2016 Oct;139(1):68-80
pubmed: 27470495
J Biol Chem. 2008 Jan 11;283(2):1197-208
pubmed: 18025084
Nature. 2005 Apr 14;434(7035):913-7
pubmed: 15829966
Curr Opin Struct Biol. 2013 Feb;23(1):134-43
pubmed: 23333033
Cancer Res. 2011 Mar 15;71(6):2308-17
pubmed: 21406402
Nucleic Acids Res. 2007;35(6):1751-60
pubmed: 17324944
Mol Cancer Res. 2015 Nov;13(11):1465-77
pubmed: 26217019
DNA Repair (Amst). 2008 Nov 1;7(11):1787-98
pubmed: 18691676
Exp Hematol. 2003 Jun;31(6):446-54
pubmed: 12829019
Nucleic Acids Res. 2012 Sep;40(16):7788-805
pubmed: 22669911
Oncogene. 2011 Jul 7;30(27):3024-35
pubmed: 21339738
Neoplasia. 2013 Mar;15(3):263-80
pubmed: 23479505
Nat Rev Cancer. 2007 Dec;7(12):899-910
pubmed: 18004397
EMBO Mol Med. 2012 Oct;4(10):1087-96
pubmed: 22933245
Mol Cell Biol. 1995 Mar;15(3):1545-53
pubmed: 7862147
Proc Natl Acad Sci U S A. 2013 Jan 29;110(5):1658-63
pubmed: 23319653
Mol Cells. 2014 Jan;37(1):9-16
pubmed: 24552704
J Pharmacol Exp Ther. 2015 Jun;353(3):446-57
pubmed: 25758918