Selective activator of human ClpP triggers cell cycle arrest to inhibit lung squamous cell carcinoma.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
03 11 2023
03 11 2023
Historique:
received:
23
11
2022
accepted:
20
10
2023
medline:
6
11
2023
pubmed:
4
11
2023
entrez:
4
11
2023
Statut:
epublish
Résumé
Chemo-activation of mitochondrial ClpP exhibits promising anticancer properties. However, we are currently unaware of any studies using selective and potent ClpP activators in lung squamous cell carcinoma. In this work, we report on such an activator, ZK53, which exhibits therapeutic effects on lung squamous cell carcinoma in vivo. The crystal structure of ZK53/ClpP complex reveals a π-π stacking effect that is essential for ligand binding selectively to the mitochondrial ClpP. ZK53 features on a simple scaffold, which is distinct from the activators with rigid scaffolds, such as acyldepsipeptides and imipridones. ZK53 treatment causes a decrease of the electron transport chain in a ClpP-dependent manner, which results in declined oxidative phosphorylation and ATP production in lung tumor cells. Mechanistically, ZK53 inhibits the adenoviral early region 2 binding factor targets and activates the ataxia-telangiectasia mutated-mediated DNA damage response, eventually triggering cell cycle arrest. Lastly, ZK53 exhibits therapeutic effects on lung squamous cell carcinoma cells in xenograft and autochthonous mouse models.
Identifiants
pubmed: 37923710
doi: 10.1038/s41467-023-42784-4
pii: 10.1038/s41467-023-42784-4
pmc: PMC10624687
doi:
Substances chimiques
ClpP protein, human
EC 3.4.21.92
Endopeptidase Clp
EC 3.4.21.92
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7069Informations de copyright
© 2023. The Author(s).
Références
ACS Chem Biol. 2019 Nov 15;14(11):2349-2360
pubmed: 31241890
Neoplasia. 2020 Dec;22(12):725-744
pubmed: 33142238
Angew Chem Int Ed Engl. 2018 Oct 26;57(44):14602-14607
pubmed: 30129683
Cell Chem Biol. 2018 Aug 16;25(8):1017-1030.e9
pubmed: 30126533
Cell. 2000 Jul 7;102(1):55-66
pubmed: 10929713
Nat Med. 2005 Oct;11(10):1082-7
pubmed: 16200071
Int J Mol Med. 2019 Jul;44(1):3-15
pubmed: 31115493
Expert Rev Mol Med. 2020 Jun 08;22:e2
pubmed: 32508294
Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):235-42
pubmed: 21460441
Crit Rev Biochem Mol Biol. 2014 Sep-Oct;49(5):400-12
pubmed: 24915503
ACS Chem Biol. 2018 Jun 15;13(6):1413-1425
pubmed: 29775273
Trends Biochem Sci. 2004 Aug;29(8):409-17
pubmed: 15362224
J Med Chem. 2022 Jun 9;65(11):7629-7655
pubmed: 35609303
Nat Rev Mol Cell Biol. 2021 Dec;22(12):796-814
pubmed: 34429537
Sci Signal. 2016 Feb 16;9(415):ra18
pubmed: 26884600
Cell Metab. 2020 Sep 1;32(3):341-352
pubmed: 32668195
Science. 2007 May 25;316(5828):1160-6
pubmed: 17525332
Clin Cancer Res. 2018 Jun 1;24(11):2482-2490
pubmed: 29420223
Cancer Res. 2004 Dec 15;64(24):9152-9
pubmed: 15604286
Structure. 2023 Feb 2;31(2):125-127
pubmed: 36736297
Nat Commun. 2022 Nov 14;13(1):6909
pubmed: 36376309
Acta Crystallogr D Biol Crystallogr. 1997 May 1;53(Pt 3):240-55
pubmed: 15299926
Pharmacol Res Perspect. 2022 Aug;10(4):e00993
pubmed: 35929764
J Biol Chem. 2000 Jun 23;275(25):19000-8
pubmed: 10748002
Cell. 2015 Jul 30;162(3):540-51
pubmed: 26232224
Nat Rev Mol Cell Biol. 2013 May;14(5):297-306
pubmed: 23594950
Neoplasia. 2017 Aug;19(8):649-658
pubmed: 28732212
Science. 2013 Jul 5;341(6141):84-7
pubmed: 23828940
Cancer Cell. 2019 May 13;35(5):721-737.e9
pubmed: 31056398
Nature. 2009 Oct 22;461(7267):1071-8
pubmed: 19847258
Nat Biotechnol. 2015 Mar;33(3):290-5
pubmed: 25690850
Oncogenesis. 2021 Feb 26;10(2):18
pubmed: 33637676
Nat Protoc. 2007;2(9):2212-21
pubmed: 17853878
Sci Adv. 2018 Jun 20;4(6):eaat1719
pubmed: 29938225
Biochem Pharmacol. 2022 Oct;204:115232
pubmed: 36030831
J Struct Biol. 2004 Dec;148(3):338-52
pubmed: 15522782
Nature. 2023 Mar;615(7953):712-719
pubmed: 36922590
Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
pubmed: 15572765
J Natl Cancer Inst. 2008 Aug 6;100(15):1104-12
pubmed: 18664653
ACS Chem Biol. 2016 Jul 15;11(7):1964-72
pubmed: 27171654
ACS Chem Biol. 2019 May 17;14(5):1020-1029
pubmed: 31021596
Curr Opin Chem Biol. 2022 Feb;66:102078
pubmed: 34446368
Proc Natl Acad Sci U S A. 2018 Apr 24;115(17):E3978-E3986
pubmed: 29632194
Nat Protoc. 2006;1(1):23-9
pubmed: 17406208
Natl Sci Rev. 2021 Jan 30;8(10):nwab014
pubmed: 34858604
Cell. 2012 Mar 16;148(6):1145-59
pubmed: 22424226
Cell Chem Biol. 2022 Sep 15;29(9):1396-1408.e8
pubmed: 35905743
Nat Methods. 2015 Apr;12(4):357-60
pubmed: 25751142
Leukemia. 2010 Apr;24(4):679-86
pubmed: 20130602
J Genet Genomics. 2021 Apr 20;48(4):268-276
pubmed: 33896738
J Agric Food Chem. 2021 Jul 14;69(27):7545-7553
pubmed: 34218658
Drug Discov Today. 2021 Apr;26(4):968-981
pubmed: 33460621
Nat Med. 2023 Jan;29(1):115-126
pubmed: 36658425
Cell Rep. 2019 Aug 13;28(7):1860-1878.e9
pubmed: 31412252
J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674
pubmed: 19461840
Neoplasia. 2022 Mar;25:18-27
pubmed: 35078134
Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):2724-9
pubmed: 22003129
Sci Transl Med. 2013 Feb 6;5(171):171ra17
pubmed: 23390247
Signal Transduct Target Ther. 2022 Oct 5;7(1):353
pubmed: 36198685
Cell Death Dis. 2020 Oct 9;11(10):841
pubmed: 33037181