Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality.
Animals
Cell Line, Tumor
Cell Survival
/ drug effects
Crystallography, X-Ray
Drug Screening Assays, Antitumor
Endopeptidase Clp
/ chemistry
Female
HCT116 Cells
HEK293 Cells
Heterocyclic Compounds, 4 or More Rings
/ administration & dosage
Humans
Imidazoles
Leukemia, Myeloid, Acute
/ drug therapy
Mice
Mitochondria
/ metabolism
Models, Molecular
Point Mutation
Protein Conformation
/ drug effects
Proteolysis
Pyridines
Pyrimidines
Tumor Suppressor Protein p53
/ metabolism
Xenograft Model Antitumor Assays
acute myeloid leukemia
cancer
imipridone
lymphoma
mitochondrial ClpP
mitochondrial proteolysis
oxidative phosphorylation
respiratory chain complex
Journal
Cancer cell
ISSN: 1878-3686
Titre abrégé: Cancer Cell
Pays: United States
ID NLM: 101130617
Informations de publication
Date de publication:
13 05 2019
13 05 2019
Historique:
received:
04
09
2018
revised:
13
11
2018
accepted:
29
03
2019
pubmed:
6
5
2019
medline:
14
2
2020
entrez:
7
5
2019
Statut:
ppublish
Résumé
The mitochondrial caseinolytic protease P (ClpP) plays a central role in mitochondrial protein quality control by degrading misfolded proteins. Using genetic and chemical approaches, we showed that hyperactivation of the protease selectively kills cancer cells, independently of p53 status, by selective degradation of its respiratory chain protein substrates and disrupts mitochondrial structure and function, while it does not affect non-malignant cells. We identified imipridones as potent activators of ClpP. Through biochemical studies and crystallography, we show that imipridones bind ClpP non-covalently and induce proteolysis by diverse structural changes. Imipridones are presently in clinical trials. Our findings suggest a general concept of inducing cancer cell lethality through activation of mitochondrial proteolysis.
Identifiants
pubmed: 31056398
pii: S1535-6108(19)30160-6
doi: 10.1016/j.ccell.2019.03.014
pmc: PMC6620028
mid: NIHMS1527929
pii:
doi:
Substances chimiques
Heterocyclic Compounds, 4 or More Rings
0
Imidazoles
0
Pyridines
0
Pyrimidines
0
TP53 protein, human
0
Tumor Suppressor Protein p53
0
TIC10 compound
9U35A31JAI
ClpP protein, human
EC 3.4.21.92
Endopeptidase Clp
EC 3.4.21.92
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
721-737.e9Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA100632
Pays : United States
Organisme : FDA HHS
ID : R01 FD006118
Pays : United States
Organisme : CIHR
Pays : Canada
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
Références
Nature. 2016 Jun 30;534(7609):710-3
pubmed: 27350246
Nature. 2014 Apr 3;508(7494):108-12
pubmed: 24670634
Cancer Cell. 2015 Jun 8;27(6):864-76
pubmed: 26058080
Nat Med. 2005 Oct;11(10):1082-7
pubmed: 16200071
Nat Med. 2017 Oct;23(10):1234-1240
pubmed: 28920959
Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
pubmed: 20383002
J Struct Biol. 2004 Dec;148(3):338-52
pubmed: 15522782
Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
pubmed: 15572765
Biochem J. 1998 Apr 1;331 ( Pt 1):309-16
pubmed: 9512494
Cell Stem Cell. 2013 Mar 7;12(3):329-41
pubmed: 23333149
Cancer Cell. 2011 Nov 15;20(5):674-88
pubmed: 22094260
Nature. 2014 Oct 30;514(7524):628-32
pubmed: 25119024
Cancer Discov. 2014 Mar;4(3):362-75
pubmed: 24346116
Nat Rev Mol Cell Biol. 2016 Apr;17(4):213-26
pubmed: 26956194
ACS Chem Biol. 2016 Feb 19;11(2):389-99
pubmed: 26606371
Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):235-42
pubmed: 21460441
Nature. 2016 Oct 27;538(7626):477-482
pubmed: 27760111
Oncotarget. 2016 Nov 8;7(45):74380-74392
pubmed: 27602582
Cell Cycle. 2017 Oct 2;16(19):1790-1799
pubmed: 28489985
Blood. 2016 Jul 14;128(2):253-64
pubmed: 27257182
Cancer Cell. 2017 Dec 11;32(6):748-760.e6
pubmed: 29232553
Sci Signal. 2016 Feb 16;9(415):ra18
pubmed: 26884600
Chem Biol. 2011 Sep 23;18(9):1167-78
pubmed: 21944755
J Synchrotron Radiat. 2011 Jul;18(Pt 4):681-4
pubmed: 21685687
Cell Metab. 2012 Jun 6;15(6):827-37
pubmed: 22682223
Clin Cancer Res. 2017 Aug 1;23(15):4163-4169
pubmed: 28331050
Nat Protoc. 2014 Sep;9(9):2100-22
pubmed: 25101824
Cancer Discov. 2017 Jul;7(7):716-735
pubmed: 28416471
Dev Cell. 2007 Oct;13(4):467-80
pubmed: 17925224
Nature. 2013 May 23;497(7450):451-7
pubmed: 23698443
Oncotarget. 2017 May 12;8(45):79298-79304
pubmed: 29108308
Autophagy. 2013 Nov 1;9(11):1750-7
pubmed: 24149988
Oncotarget. 2017 Sep 12;8(47):81776-81793
pubmed: 29137221
Sci Rep. 2015 Dec 02;5:17397
pubmed: 26627475
Protein Sci. 2008 Jul;17(7):1241-8
pubmed: 18467498
Cell Chem Biol. 2018 Aug 16;25(8):1017-1030.e9
pubmed: 30126533
Sci Signal. 2016 Feb 16;9(415):ra17
pubmed: 26884599
Cancer Discov. 2016 Oct;6(10):1106-1117
pubmed: 27520294
Nucleic Acids Res. 2010 Sep;38(16):e164
pubmed: 20601685
Oncotarget. 2018 Apr 6;9(26):18454-18479
pubmed: 29719618
Leukemia. 2005 Oct;19(10):1794-805
pubmed: 16094415
Blood. 2015 Mar 26;125(13):2120-30
pubmed: 25631767
Structure. 2010 Jul 14;18(7):798-808
pubmed: 20637416
Neoplasia. 2018 Jan;20(1):80-91
pubmed: 29216597
ACS Chem Biol. 2016 Jul 15;11(7):1964-72
pubmed: 27171654
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21
pubmed: 20124702
J Biol Chem. 2005 Oct 21;280(42):35424-32
pubmed: 16115876
J Mol Biol. 1999 Oct 1;292(4):819-25
pubmed: 10525407
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):125-32
pubmed: 20124692
Cancer Cell. 2006 Nov;10(5):375-88
pubmed: 17097560
J Cell Biol. 2012 Mar 19;196(6):801-10
pubmed: 22412018
Bioinformatics. 2004 Jun 12;20(9):1466-7
pubmed: 14976030
Proteomics. 2013 Jan;13(1):22-4
pubmed: 23148064
Nat Struct Mol Biol. 2010 Apr;17(4):471-8
pubmed: 20305655
Nat Commun. 2015 Feb 19;6:6320
pubmed: 25695750
Cancer Biol Ther. 2012 Aug;13(10):858-70
pubmed: 22785211
EMBO Rep. 2016 Jul;17(7):953-64
pubmed: 27154400
J Clin Invest. 2010 Jan;120(1):142-56
pubmed: 20038799
Science. 2007 Sep 28;317(5846):1881-6
pubmed: 17901324
J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674
pubmed: 19461840
EMBO J. 2002 Sep 2;21(17):4411-9
pubmed: 12198143
Neoplasia. 2017 Oct;19(10):772-780
pubmed: 28863346
Sci Transl Med. 2013 Feb 6;5(171):171ra17
pubmed: 23390247
Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16678-83
pubmed: 16263929
Bioinformatics. 2008 Nov 1;24(21):2534-6
pubmed: 18606607
Nature. 2013 Nov 21;503(7476):365-70
pubmed: 24226776