Next Article in Journal
Circulating Neutrophils Do Not Predict Subclinical Coronary Artery Disease in Women with Former Preeclampsia
Next Article in Special Issue
The Vacuolar H+ ATPase α3 Subunit Negatively Regulates Migration and Invasion of Human Pancreatic Ductal Adenocarcinoma Cells
Previous Article in Journal
Flexible Players within the Sheaths: The Intrinsically Disordered Proteins of Myelin in Health and Disease
Previous Article in Special Issue
Dexamethasone Inhibits Spheroid Formation of Thyroid Cancer Cells Exposed to Simulated Microgravity
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cells
Volume 9
Issue 2
10.3390/cells9020469
cells-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

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

by
Dusana Majera
1,†,
Zdenek Skrott
1,†,
Katarina Chroma
1,
Joanna Maria Merchut-Maya
2,
Martin Mistrik
1,* and
Jiri Bartek
1,2,3,*
1
Laboratory of Genome Integrity, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, 77 147 Olomouc, Czech Republic
2
Danish Cancer Society Research Center, 2100 Copenhagen, Denmark
3
Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Karolinska Institute, 171 77 Stockholm, Sweden
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cells 2020, 9(2), 469; https://doi.org/10.3390/cells9020469
Submission received: 21 January 2020 / Revised: 17 February 2020 / Accepted: 17 February 2020 / Published: 18 February 2020
(This article belongs to the Special Issue Killing Cancer: Discovery and Selection of New Target Molecules)
Browse Figures
Versions Notes

Abstract

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.
Keywords: targeted cancer therapy; disulfiram; NPL4; replication stress; DNA damage; BRCA1; BRCA2; ATR pathway targeted cancer therapy; disulfiram; NPL4; replication stress; DNA damage; BRCA1; BRCA2; ATR pathway

Share and Cite

MDPI and ACS Style

Majera, D.; Skrott, Z.; Chroma, K.; Merchut-Maya, J.M.; Mistrik, M.; Bartek, J. 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. Cells 2020, 9, 469. https://doi.org/10.3390/cells9020469

AMA Style

Majera D, Skrott Z, Chroma K, Merchut-Maya JM, Mistrik M, Bartek J. 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. Cells. 2020; 9(2):469. https://doi.org/10.3390/cells9020469

Chicago/Turabian Style

Majera, Dusana, Zdenek Skrott, Katarina Chroma, Joanna Maria Merchut-Maya, Martin Mistrik, and Jiri Bartek. 2020. "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" Cells 9, no. 2: 469. https://doi.org/10.3390/cells9020469

APA Style

Majera, D., Skrott, Z., Chroma, K., Merchut-Maya, J. M., Mistrik, M., & Bartek, J. (2020). 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. Cells, 9(2), 469. https://doi.org/10.3390/cells9020469

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop