Interaction with Ribosomal Proteins Accompanies Stress Induction of the Anticancer Metallodrug BOLD-100/KP1339 in the Endoplasmic Reticulum.
Antineoplastic Agents
/ chemistry
Endoplasmic Reticulum
/ drug effects
Endoplasmic Reticulum Chaperone BiP
Endoplasmic Reticulum Stress
/ drug effects
HCT116 Cells
Humans
Organometallic Compounds
/ chemistry
Polyribosomes
/ metabolism
Ribosomal Protein L10
/ metabolism
Ribosomal Proteins
/ metabolism
Ruthenium
/ chemistry
Transcription Factors, TFII
/ metabolism
Transcriptome
bioinorganic chemistry
metals in medicine
multi-omics
ribosome
ruthenium
Journal
Angewandte Chemie (International ed. in English)
ISSN: 1521-3773
Titre abrégé: Angew Chem Int Ed Engl
Pays: Germany
ID NLM: 0370543
Informations de publication
Date de publication:
01 03 2021
01 03 2021
Historique:
received:
30
11
2020
pubmed:
29
12
2020
medline:
21
7
2021
entrez:
28
12
2020
Statut:
ppublish
Résumé
The ruthenium-based anticancer agent BOLD-100/KP1339 has shown promising results in several in vitro and in vivo tumour models as well as in early clinical trials. However, its mode of action remains to be fully elucidated. Recent evidence identified stress induction in the endoplasmic reticulum (ER) and concomitant down-modulation of HSPA5 (GRP78) as key drug effects. By exploiting the naturally formed adduct between BOLD-100 and human serum albumin as an immobilization strategy, we were able to perform target-profiling experiments that revealed the ribosomal proteins RPL10, RPL24, and the transcription factor GTF2I as potential interactors of this ruthenium(III) anticancer agent. Integrating these findings with proteomic profiling and transcriptomic experiments supported ribosomal disturbance and concomitant induction of ER stress. The formation of polyribosomes and ER swelling of treated cancer cells revealed by TEM validated this finding. Thus, the direct interaction of BOLD-100 with ribosomal proteins seems to accompany ER stress-induction and modulation of GRP78 in cancer cells.
Identifiants
pubmed: 33369073
doi: 10.1002/anie.202015962
pmc: PMC7986094
doi:
Substances chimiques
Antineoplastic Agents
0
Endoplasmic Reticulum Chaperone BiP
0
GTF2I protein, human
0
HSPA5 protein, human
0
KP 1339
0
Organometallic Compounds
0
RPL10 protein, human
0
Ribosomal Proteins
0
Transcription Factors, TFII
0
ribosomal protein L24
0
Ruthenium
7UI0TKC3U5
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5063-5068Informations de copyright
© 2020 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.
Références
J Biol Chem. 2005 Apr 29;280(17):16821-8
pubmed: 15664986
Metallomics. 2019 Jan 23;11(1):118-127
pubmed: 30106070
ESMO Open. 2017 Feb 23;1(6):e000154
pubmed: 28848672
J Inorg Biochem. 2016 Jul;160:250-5
pubmed: 26993078
Chem Sci. 2015 Apr 1;6(4):2449-2456
pubmed: 29308157
Genome Res. 2003 Nov;13(11):2498-504
pubmed: 14597658
Angew Chem Int Ed Engl. 2019 Aug 5;58(32):10914-10918
pubmed: 31165553
Metallomics. 2019 Jun 19;11(6):1044-1048
pubmed: 30942231
Anticancer Res. 1989 May-Jun;9(3):761-5
pubmed: 2764521
Angew Chem Int Ed Engl. 2017 Mar 27;56(14):3892-3896
pubmed: 28247451
Sci Rep. 2017 Jan 23;7:40966
pubmed: 28112202
Chem Sci. 2014 Jun 6;5(8):3135-3143
pubmed: 35919909
Chem Soc Rev. 2018 Feb 5;47(3):909-928
pubmed: 29170783
J Biol Inorg Chem. 2010 Feb;15(2):131-45
pubmed: 19707803
J Cell Biochem. 2009 Feb 15;106(3):381-9
pubmed: 19097122
Chem Sci. 2016 May 1;7(5):3052-3061
pubmed: 29997796
Mol Cell Biol. 2001 May;21(9):3220-33
pubmed: 11287625
Curr Opin Chem Biol. 2020 Apr;55:171-179
pubmed: 32200302
Invest New Drugs. 2016 Jun;34(3):261-8
pubmed: 26988975
J Med Chem. 2016 Jun 23;59(12):5894-903
pubmed: 27196130
Angew Chem Int Ed Engl. 2021 Mar 1;60(10):5063-5068
pubmed: 33369073
J Biol Inorg Chem. 2010 Jun;15(5):737-48
pubmed: 20221888
J Cancer Res Clin Oncol. 2005 Feb;131(2):101-10
pubmed: 15503135
Oncotarget. 2018 Jul 3;9(51):29698-29714
pubmed: 30038714
Nucleic Acids Res. 2019 Jan 8;47(D1):D607-D613
pubmed: 30476243
Angew Chem Int Ed Engl. 2016 Jan 22;55(4):1387-91
pubmed: 26663758
Chemistry. 2017 Feb 3;23(8):1881-1890
pubmed: 28071820
Metallomics. 2011 Jun;3(6):591-9
pubmed: 21399784
Metallomics. 2017 Jan 25;9(1):38-47
pubmed: 27830853
Angew Chem Int Ed Engl. 2013 Apr 26;52(18):4916-20
pubmed: 23553936
Chem Sci. 2017 Jun 1;8(6):4626-4633
pubmed: 28626571
Metallomics. 2011 Oct;3(10):1049-55
pubmed: 21935553
Angew Chem Int Ed Engl. 2017 Jul 3;56(28):8267-8271
pubmed: 28547791