GlutaredoxinV1, Main, Exploration, bibRecord, 000248

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

Identifieur interne : 000248 ( Main/Exploration ); précédent : 000247; suivant : 000249

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

Auteurs : Lena Haffo [Suède] ; Jun Lu [Suède, République populaire de Chine] ; Vladimir J N. Bykov [Suède] ; Sebastin S. Martin [Suède] ; Xiaoyuan Ren [Suède] ; Lucia Coppo [Suède] ; Klas G. Wiman [Suède] ; Arne Holmgren [Suède]

Source :

Scientific reports [ 2045-2322 ] ; 2018.

RBID : pubmed:30140002

Descripteurs français

KwdFr :
- Antioxydants (métabolisme), Espèces réactives de l'oxygène (métabolisme), Glutarédoxines (métabolisme), Humains (MeSH), Lignée cellulaire tumorale (MeSH), Mitochondries (métabolisme), Oxydoréduction (MeSH), Quinuclidines (métabolisme), Ribonucleotide reductases (métabolisme), Réparation de l'ADN (génétique), Réparation de l'ADN (physiologie), Spectrométrie de masse (MeSH), Technique de Western (MeSH), Thiols (métabolisme), Thiorédoxines (métabolisme).
MESH :
- génétique : Réparation de l'ADN.
- métabolisme : Antioxydants, Espèces réactives de l'oxygène, Glutarédoxines, Mitochondries, Quinuclidines, Ribonucleotide reductases, Thiols, Thiorédoxines.
- physiologie : Réparation de l'ADN.
- Humains, Lignée cellulaire tumorale, Oxydoréduction, Spectrométrie de masse, Technique de Western.

English descriptors

KwdEn :
- Antioxidants (metabolism), Blotting, Western (MeSH), Cell Line, Tumor (MeSH), DNA Repair (genetics), DNA Repair (physiology), Glutaredoxins (metabolism), Humans (MeSH), Mass Spectrometry (MeSH), Mitochondria (metabolism), Oxidation-Reduction (MeSH), Quinuclidines (metabolism), Reactive Oxygen Species (metabolism), Ribonucleotide Reductases (metabolism), Sulfhydryl Compounds (metabolism), Thioredoxins (metabolism).
MESH :
- chemical , metabolism : Antioxidants, Glutaredoxins, Quinuclidines, Reactive Oxygen Species, Ribonucleotide Reductases, Sulfhydryl Compounds, Thioredoxins.
- genetics : DNA Repair.
- metabolism : Mitochondria.
- physiology : DNA Repair.
- Blotting, Western, Cell Line, Tumor, Humans, Mass Spectrometry, Oxidation-Reduction.

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-1^Met) 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.

DOI: 10.1038/s41598-018-31048-7
PubMed: 30140002
PubMed Central: PMC6107631

Affiliations:

Links toward previous steps (curation, corpus...)

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Le document en format XML

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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antioxidants (metabolism)</term>
<term>Blotting, Western (MeSH)</term>
<term>Cell Line, Tumor (MeSH)</term>
<term>DNA Repair (genetics)</term>
<term>DNA Repair (physiology)</term>
<term>Glutaredoxins (metabolism)</term>
<term>Humans (MeSH)</term>
<term>Mass Spectrometry (MeSH)</term>
<term>Mitochondria (metabolism)</term>
<term>Oxidation-Reduction (MeSH)</term>
<term>Quinuclidines (metabolism)</term>
<term>Reactive Oxygen Species (metabolism)</term>
<term>Ribonucleotide Reductases (metabolism)</term>
<term>Sulfhydryl Compounds (metabolism)</term>
<term>Thioredoxins (metabolism)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Antioxydants (métabolisme)</term>
<term>Espèces réactives de l'oxygène (métabolisme)</term>
<term>Glutarédoxines (métabolisme)</term>
<term>Humains (MeSH)</term>
<term>Lignée cellulaire tumorale (MeSH)</term>
<term>Mitochondries (métabolisme)</term>
<term>Oxydoréduction (MeSH)</term>
<term>Quinuclidines (métabolisme)</term>
<term>Ribonucleotide reductases (métabolisme)</term>
<term>Réparation de l'ADN (génétique)</term>
<term>Réparation de l'ADN (physiologie)</term>
<term>Spectrométrie de masse (MeSH)</term>
<term>Technique de Western (MeSH)</term>
<term>Thiols (métabolisme)</term>
<term>Thiorédoxines (métabolisme)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Antioxidants</term>
<term>Glutaredoxins</term>
<term>Quinuclidines</term>
<term>Reactive Oxygen Species</term>
<term>Ribonucleotide Reductases</term>
<term>Sulfhydryl Compounds</term>
<term>Thioredoxins</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>DNA Repair</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Réparation de l'ADN</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Mitochondria</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Antioxydants</term>
<term>Espèces réactives de l'oxygène</term>
<term>Glutarédoxines</term>
<term>Mitochondries</term>
<term>Quinuclidines</term>
<term>Ribonucleotide reductases</term>
<term>Thiols</term>
<term>Thiorédoxines</term>
</keywords>
<keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Réparation de l'ADN</term>
</keywords>
<keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>DNA Repair</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Blotting, Western</term>
<term>Cell Line, Tumor</term>
<term>Humans</term>
<term>Mass Spectrometry</term>
<term>Oxidation-Reduction</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Humains</term>
<term>Lignée cellulaire tumorale</term>
<term>Oxydoréduction</term>
<term>Spectrométrie de masse</term>
<term>Technique de Western</term>
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<front><div type="abstract" xml:lang="en">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-1<sup>Met</sup>
) 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.</div>
</front>
</TEI>
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<Month>10</Month>
<Day>28</Day>
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<Title>Scientific reports</Title>
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<ArticleTitle>Inhibition of the glutaredoxin and thioredoxin systems and ribonucleotide reductase by mutant p53-targeting compound APR-246.</ArticleTitle>
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<Abstract><AbstractText>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-1<sup>Met</sup>
) 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.</AbstractText>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Haffo</LastName>
<ForeName>Lena</ForeName>
<Initials>L</Initials>
<AffiliationInfo><Affiliation>Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77, Stockholm, Sweden.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Department of Oncology-Pathology, Cancer Center Karolinska (CCK), Karolinska Institutet, SE-171 76, Stockholm, Sweden.</Affiliation>
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Inhibition of the glutaredoxin and thioredoxin systems and ribonucleotide reductase by mutant p53-targeting compound APR-246.

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

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