Targeting the NPL4 Adaptor of p97/VCP Segregase by Disulfiram as an Emerging Cancer Vulnerability Evokes Replication Stress and DNA Damage while Silencing the ATR Pathway.
Adaptor Proteins, Signal Transducing
/ metabolism
Alcohol Deterrents
/ pharmacology
Ataxia Telangiectasia Mutated Proteins
/ antagonists & inhibitors
Cell Line, Tumor
Checkpoint Kinase 1
/ metabolism
DNA Damage
/ drug effects
DNA Replication
/ drug effects
DNA-Binding Proteins
/ metabolism
Disulfiram
/ pharmacology
Humans
Neoplasms
/ metabolism
Nuclear Proteins
/ antagonists & inhibitors
Protein Aggregates
/ drug effects
Protein Aggregation, Pathological
/ chemically induced
Signal Transduction
/ drug effects
Valosin Containing Protein
/ metabolism
ATR pathway
BRCA1
BRCA2
DNA damage
NPL4
disulfiram
replication stress
targeted cancer therapy
Journal
Cells
ISSN: 2073-4409
Titre abrégé: Cells
Pays: Switzerland
ID NLM: 101600052
Informations de publication
Date de publication:
18 02 2020
18 02 2020
Historique:
received:
21
01
2020
revised:
17
02
2020
accepted:
17
02
2020
entrez:
23
2
2020
pubmed:
23
2
2020
medline:
20
2
2021
Statut:
epublish
Résumé
Research on repurposing the old alcohol-aversion drug disulfiram (DSF) for cancer treatment has identified inhibition of NPL4, an adaptor of the p97/VCP segregase essential for turnover of proteins involved in multiple pathways, as an unsuspected cancer cell vulnerability. While we reported that NPL4 is targeted by the anticancer metabolite of DSF, the bis-diethyldithiocarbamate-copper complex (CuET), the exact, apparently multifaceted mechanism(s) through which the CuET-induced aggregation of NPL4 kills cancer cells remains to be fully elucidated. Given the pronounced sensitivity to CuET in tumor cell lines lacking the genome integrity caretaker proteins BRCA1 and BRCA2, here we investigated the impact of NPL4 targeting by CuET on DNA replication dynamics and DNA damage response pathways in human cancer cell models. Our results show that CuET treatment interferes with DNA replication, slows down replication fork progression and causes accumulation of single-stranded DNA (ssDNA). Such a replication stress (RS) scenario is associated with DNA damage, preferentially in the S phase, and activates the homologous recombination (HR) DNA repair pathway. At the same time, we find that cellular responses to the CuET-triggered RS are seriously impaired due to concomitant malfunction of the ATRIP-ATR-CHK1 signaling pathway that reflects an unorthodox checkpoint silencing mode through ATR (Ataxia telangiectasia and Rad3 related) kinase sequestration within the CuET-evoked NPL4 protein aggregates.
Identifiants
pubmed: 32085572
pii: cells9020469
doi: 10.3390/cells9020469
pmc: PMC7072750
pii:
doi:
Substances chimiques
ATRIP protein, human
0
Adaptor Proteins, Signal Transducing
0
Alcohol Deterrents
0
DNA-Binding Proteins
0
NPLOC4 protein, human
0
Nuclear Proteins
0
Protein Aggregates
0
ATR protein, human
EC 2.7.11.1
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
CHEK1 protein, human
EC 2.7.11.1
Checkpoint Kinase 1
EC 2.7.11.1
VCP protein, human
EC 3.6.4.6
Valosin Containing Protein
EC 3.6.4.6
Disulfiram
TR3MLJ1UAI
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Déclaration de conflit d'intérêts
The authors declare no conflict of interest.
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