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Repurposing an antidandruff agent to treating cancer: zinc pyrithione inhibits tumor growth via targeting proteasome-associated deubiquitinases
- Source :
- Oncotarget
- Publication Year :
- 2017
- Publisher :
- Impact Journals LLC, 2017.
-
Abstract
- The ubiquitin-proteasome system (UPS) plays a central role in various cellular processes through selectively degrading proteins involved in critical cellular functions. Targeting UPS has been validated as a novel strategy for treating human cancer, as inhibitors of the 20S proteasome catalytic activity are currently in clinical use for treatment of multiple myeloma and other cancers, and the deubiquitinase activity associated with the proteasome is also a valid target for anticancer agents. Recent studies suggested that zinc pyrithione, an FDA-approved antidandruff agent, may have antitumor activity, but the detailed molecular mechanisms remain unclear. Here we report that zinc pyrithione (ZnPT) targets the proteasome-associated DUBs (USP14 and UCHL5) and inhibits their activities, resulting in a rapid accumulation of protein-ubiquitin conjugates, but without inhibiting the proteolytic activities of 20S proteasomes. Furthermore, ZnPT exhibits cytotoxic effects against various cancer cell lines in vitro, selectively kills bone marrow cells from leukemia patients ex vivo, and efficiently inhibits the growth of lung adenocarcinoma cancer cell xenografts in nude mice. This study has identified zinc pyrithione, an FDA-approved pharmacological agent with potential antitumor properties as a proteasomal DUB inhibitor.
- Subjects :
- 0301 basic medicine
Models, Molecular
tumor
Proteasome Endopeptidase Complex
Pyridines
Blotting, Western
Fluorescent Antibody Technique
Mice, Nude
Antineoplastic Agents
Apoptosis
03 medical and health sciences
Mice
Keratolytic Agents
Cell Line, Tumor
medicine
Organometallic Compounds
Cytotoxic T cell
Animals
Humans
deubiquitinases
business.industry
Cancer
Neoplasms, Experimental
medicine.disease
Immunohistochemistry
Xenograft Model Antitumor Assays
In vitro
Leukemia
030104 developmental biology
proteasome
Oncology
Proteasome
Cancer cell
Dandruff
Cancer research
DNA damage
business
zinc pyrithione
Proteasome Inhibitors
Ubiquitin Thiolesterase
Ex vivo
Research Paper
Subjects
Details
- Language :
- English
- ISSN :
- 19492553
- Volume :
- 8
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Oncotarget
- Accession number :
- edsair.doi.dedup.....07677ea37f1c150f10966a046fbdf69b