Inhibition of the glutaredoxin and thioredoxin systems and ribonucleotide reductase by mutant p53-targeting compound APR-246

Abstract The tumor suppressor p53 is commonly inactivated in human tumors, allowing evasion of p53-dependent apoptosis and tumor progression. The small molecule APR-246 (PRIMA-1Met) can reactive mutant p53 in tumor cells and trigger cell death by apoptosis. The thioredoxin (Trx) and glutaredoxin (Gr...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Lena Haffo, Jun Lu, Vladimir J. N. Bykov, Sebastin S. Martin, Xiaoyuan Ren, Lucia Coppo, Klas G. Wiman, Arne Holmgren
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5919892998d44e63a8772d90b40e9d3a
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:5919892998d44e63a8772d90b40e9d3a
record_format	dspace
spelling	oai:doaj.org-article:5919892998d44e63a8772d90b40e9d3a2021-12-02T11:40:54ZInhibition of the glutaredoxin and thioredoxin systems and ribonucleotide reductase by mutant p53-targeting compound APR-24610.1038/s41598-018-31048-72045-2322https://doaj.org/article/5919892998d44e63a8772d90b40e9d3a2018-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-31048-7https://doaj.org/toc/2045-2322Abstract The tumor suppressor p53 is commonly inactivated in human tumors, allowing evasion of p53-dependent apoptosis and tumor progression. The small molecule APR-246 (PRIMA-1Met) can reactive mutant p53 in tumor cells and trigger cell death by apoptosis. The thioredoxin (Trx) and glutaredoxin (Grx) systems are important as antioxidants for maintaining cellular redox balance and providing electrons for thiol-dependent reactions like those catalyzed by ribonucleotide reductase and peroxiredoxins (Prxs). We show here that the Michael acceptor methylene quinuclidinone (MQ), the active form of APR-246, is a potent direct inhibitor of Trx1 and Grx1 by reacting with sulfhydryl groups in the enzymes. The inhibition of Trx1 and Grx1 by APR-246/MQ is reversible and the inhibitory efficiency is dependent on the presence of glutathione. APR-246/MQ also inhibits Trxs in mutant p53-expressing Saos-2 His-273 cells, showing modification of Trx1 and mitochondrial Trx2. Inhibition of the Trx and Grx systems leads to insufficient reducing power to deoxyribonucleotide production for DNA replication and repair and peroxiredoxin for removal of ROS. We also demonstrate that APR-246 and MQ inhibit ribonucleotide reductase (RNR) in vitro and in living cells. Our results suggest that APR-246 induces tumor cell death through both reactivations of mutant p53 and inhibition of cellular thiol-dependent redox systems, providing a novel strategy for cancer therapy.Lena HaffoJun LuVladimir J. N. BykovSebastin S. MartinXiaoyuan RenLucia CoppoKlas G. WimanArne HolmgrenNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-10 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Lena Haffo Jun Lu Vladimir J. N. Bykov Sebastin S. Martin Xiaoyuan Ren Lucia Coppo Klas G. Wiman Arne Holmgren Inhibition of the glutaredoxin and thioredoxin systems and ribonucleotide reductase by mutant p53-targeting compound APR-246
description	Abstract The tumor suppressor p53 is commonly inactivated in human tumors, allowing evasion of p53-dependent apoptosis and tumor progression. The small molecule APR-246 (PRIMA-1Met) can reactive mutant p53 in tumor cells and trigger cell death by apoptosis. The thioredoxin (Trx) and glutaredoxin (Grx) systems are important as antioxidants for maintaining cellular redox balance and providing electrons for thiol-dependent reactions like those catalyzed by ribonucleotide reductase and peroxiredoxins (Prxs). We show here that the Michael acceptor methylene quinuclidinone (MQ), the active form of APR-246, is a potent direct inhibitor of Trx1 and Grx1 by reacting with sulfhydryl groups in the enzymes. The inhibition of Trx1 and Grx1 by APR-246/MQ is reversible and the inhibitory efficiency is dependent on the presence of glutathione. APR-246/MQ also inhibits Trxs in mutant p53-expressing Saos-2 His-273 cells, showing modification of Trx1 and mitochondrial Trx2. Inhibition of the Trx and Grx systems leads to insufficient reducing power to deoxyribonucleotide production for DNA replication and repair and peroxiredoxin for removal of ROS. We also demonstrate that APR-246 and MQ inhibit ribonucleotide reductase (RNR) in vitro and in living cells. Our results suggest that APR-246 induces tumor cell death through both reactivations of mutant p53 and inhibition of cellular thiol-dependent redox systems, providing a novel strategy for cancer therapy.
format	article
author	Lena Haffo Jun Lu Vladimir J. N. Bykov Sebastin S. Martin Xiaoyuan Ren Lucia Coppo Klas G. Wiman Arne Holmgren
author_facet	Lena Haffo Jun Lu Vladimir J. N. Bykov Sebastin S. Martin Xiaoyuan Ren Lucia Coppo Klas G. Wiman Arne Holmgren
author_sort	Lena Haffo
title	Inhibition of the glutaredoxin and thioredoxin systems and ribonucleotide reductase by mutant p53-targeting compound APR-246
title_short	Inhibition of the glutaredoxin and thioredoxin systems and ribonucleotide reductase by mutant p53-targeting compound APR-246
title_full	Inhibition of the glutaredoxin and thioredoxin systems and ribonucleotide reductase by mutant p53-targeting compound APR-246
title_fullStr	Inhibition of the glutaredoxin and thioredoxin systems and ribonucleotide reductase by mutant p53-targeting compound APR-246
title_full_unstemmed	Inhibition of the glutaredoxin and thioredoxin systems and ribonucleotide reductase by mutant p53-targeting compound APR-246
title_sort	inhibition of the glutaredoxin and thioredoxin systems and ribonucleotide reductase by mutant p53-targeting compound apr-246
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/5919892998d44e63a8772d90b40e9d3a
work_keys_str_mv	AT lenahaffo inhibitionoftheglutaredoxinandthioredoxinsystemsandribonucleotidereductasebymutantp53targetingcompoundapr246 AT junlu inhibitionoftheglutaredoxinandthioredoxinsystemsandribonucleotidereductasebymutantp53targetingcompoundapr246 AT vladimirjnbykov inhibitionoftheglutaredoxinandthioredoxinsystemsandribonucleotidereductasebymutantp53targetingcompoundapr246 AT sebastinsmartin inhibitionoftheglutaredoxinandthioredoxinsystemsandribonucleotidereductasebymutantp53targetingcompoundapr246 AT xiaoyuanren inhibitionoftheglutaredoxinandthioredoxinsystemsandribonucleotidereductasebymutantp53targetingcompoundapr246 AT luciacoppo inhibitionoftheglutaredoxinandthioredoxinsystemsandribonucleotidereductasebymutantp53targetingcompoundapr246 AT klasgwiman inhibitionoftheglutaredoxinandthioredoxinsystemsandribonucleotidereductasebymutantp53targetingcompoundapr246 AT arneholmgren inhibitionoftheglutaredoxinandthioredoxinsystemsandribonucleotidereductasebymutantp53targetingcompoundapr246
_version_	1718395516801253376

Inhibition of the glutaredoxin and thioredoxin systems and ribonucleotide reductase by mutant p53-targeting compound APR-246

Ejemplares similares