IKKα Kinase Regulates the DNA Damage Response and Drives Chemo-resistance in Cancer.
Animals
DNA Damage
DNA Repair
/ drug effects
Drug Resistance, Neoplasm
/ drug effects
Fluorouracil
/ pharmacology
HCT116 Cells
Humans
I-kappa B Kinase
/ genetics
Irinotecan
/ pharmacology
MAP Kinase Signaling System
/ drug effects
MCF-7 Cells
Mice
Mice, Nude
Neoplasm Metastasis
Neoplasm Proteins
/ genetics
Neoplasms
/ drug therapy
Telomere
/ genetics
Xenograft Model Antitumor Assays
ATM
BRAF
DNA-damage Repair
IKK
cancer treatment
combination therapy
ortho-xenografts
patient-derived organoids
phosphorylation
therapy resistance
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
22 08 2019
22 08 2019
Historique:
received:
25
04
2018
revised:
13
03
2019
accepted:
30
05
2019
pubmed:
16
7
2019
medline:
29
1
2020
entrez:
15
7
2019
Statut:
ppublish
Résumé
Phosphorylated IKKα(p45) is a nuclear active form of the IKKα kinase that is induced by the MAP kinases BRAF and TAK1 and promotes tumor growth independent of canonical NF-κB signaling. Insights into the sources of IKKα(p45) activation and its downstream substrates in the nucleus remain to be defined. Here, we discover that IKKα(p45) is rapidly activated by DNA damage independent of ATM-ATR, but dependent on BRAF-TAK1-p38-MAPK, and is required for robust ATM activation and efficient DNA repair. Abolishing BRAF or IKKα activity attenuates ATM, Chk1, MDC1, Kap1, and 53BP1 phosphorylation, compromises 53BP1 and RIF1 co-recruitment to sites of DNA lesions, and inhibits 53BP1-dependent fusion of dysfunctional telomeres. Furthermore, IKKα or BRAF inhibition synergistically enhances the therapeutic potential of 5-FU and irinotecan to eradicate chemotherapy-resistant metastatic human tumors in vivo. Our results implicate BRAF and IKKα kinases in the DDR and reveal a combination strategy for cancer treatment.
Identifiants
pubmed: 31302002
pii: S1097-2765(19)30433-2
doi: 10.1016/j.molcel.2019.05.036
pmc: PMC6715775
pii:
doi:
Substances chimiques
Neoplasm Proteins
0
Irinotecan
7673326042
I-kappa B Kinase
EC 2.7.11.10
Fluorouracil
U3P01618RT
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
669-682.e5Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
Pays : United Kingdom
Organisme : Cancer Research UK
Pays : United Kingdom
Informations de copyright
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
Références
Science. 2001 Nov 9;294(5545):1299-304
pubmed: 11701921
Cell Rep. 2012 Oct 25;2(4):840-54
pubmed: 23041317
Cancer Cell. 2018 Jun 11;33(6):1094-1110.e8
pubmed: 29805078
J Clin Oncol. 2008 Apr 1;26(10):1626-34
pubmed: 18316791
Genes Dev. 2005 Dec 15;19(24):3043-54
pubmed: 16357220
Nature. 2001 May 3;411(6833):102-7
pubmed: 11333986
JCI Insight. 2018 Feb 8;3(3):
pubmed: 29415881
Nature. 2007 Apr 5;446(7136):690-4
pubmed: 17377533
Mol Microbiol. 2008 Apr;68(2):246-54
pubmed: 18366437
Biochem Biophys Res Commun. 2010 Aug 27;399(3):324-30
pubmed: 20643100
Lancet Oncol. 2014 Aug;15(9):954-65
pubmed: 25037139
Lancet. 2014 Apr 26;383(9927):1490-1502
pubmed: 24225001
Nat Rev Mol Cell Biol. 2014 Jan;15(1):7-18
pubmed: 24326623
J Cell Sci. 2012 Aug 1;125(Pt 15):3529-34
pubmed: 22553214
J Clin Oncol. 2009 Dec 10;27(35):5931-7
pubmed: 19884549
Science. 2018 Feb 23;359(6378):920-926
pubmed: 29472484
Science. 2006 Feb 24;311(5764):1141-6
pubmed: 16497931
Arch Dermatol Res. 2015 Oct;307(8):721-9
pubmed: 26094020
Sci Rep. 2015 Jul 20;5:12300
pubmed: 26189595
Sci Signal. 2015 Apr 21;8(373):ra38
pubmed: 25900832
J Clin Oncol. 2008 Dec 10;26(35):5705-12
pubmed: 19001320
Mol Cell. 2011 May 6;42(3):319-29
pubmed: 21549309
Nat Cell Biol. 2005 Jul;7(7):712-8
pubmed: 15968270
Br J Cancer. 2018 Mar 20;118(6):839-846
pubmed: 29438366
Sci Transl Med. 2015 Mar 18;7(279):279ra41
pubmed: 25787767
Gastroenterology. 2011 Nov;141(5):1762-72
pubmed: 21889923
Mol Cell. 2013 Mar 7;49(5):872-83
pubmed: 23333306
J Biol Chem. 2003 Aug 22;278(34):32227-35
pubmed: 12794074
J Exp Med. 2010 Apr 12;207(4):855-65
pubmed: 20368578
Cancer Discov. 2016 Dec;6(12):1352-1365
pubmed: 27729313
Nat Med. 2017 Oct 6;23(10):1124-1134
pubmed: 28985214
Cell. 2017 Jan 12;168(1-2):37-57
pubmed: 28086098
Mol Cell. 2012 Aug 24;47(4):497-510
pubmed: 22920291
Nat Med. 2012 Jan 22;18(2):221-3
pubmed: 22270724
J Cell Biol. 2008 Dec 1;183(5):777-83
pubmed: 19047460
Cancer Res. 2018 Jun 1;78(11):2939-2951
pubmed: 29588349
Mol Cell. 2000 Jul;6(1):109-16
pubmed: 10949032
Mol Cell Biol. 2011 Jul;31(14):2774-86
pubmed: 21606198
Mol Cell. 2013 Mar 7;49(5):858-71
pubmed: 23333305
Science. 2013 Feb 8;339(6120):700-4
pubmed: 23306437
Cell. 1994 Sep 23;78(6):1027-37
pubmed: 7923353