Format

Send to

Choose Destination
Oncogene. 2016 Nov 10;35(45):5916-5927. doi: 10.1038/onc.2016.114. Epub 2016 Apr 18.

A novel nickel complex works as a proteasomal deubiquitinase inhibitor for cancer therapy.

Author information

1
State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangzhou, China.
2
Guangzhou Research Institute of Cardiovascular Disease, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
3
Institute of Environmental and Analytical Sciences, College of Chemistry and Chemical Engineering, Henan University, Kaifeng, China.
4
Key Lab of Natural Drug and Immune Engineering of Henan Province, Kaifeng, China.
5
Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, China.
6
The Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
7
Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, MI, USA.
8
Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, SD, USA.

Abstract

Based on the central role of the ubiquitin-proteasome system (UPS) in the degradation of cellular proteins, proteasome inhibition has been considered an attractive approach for anticancer therapy. Deubiquitinases (DUBs) remove ubiquitin conjugates from diverse substrates; therefore, they are essential regulators of the UPS. DUB inhibitors, especially the inhibitors of proteasomal DUBs are becoming a research hotspot in targeted cancer therapy. Previous studies have shown that metal complexes, such as copper and zinc complexes, can induce cancer cell apoptosis through inhibiting UPS function. Moreover, we have found that copper pyrithione inhibits both 19S proteasome-associated DUBs and 20S proteasome activity with a mechanism distinct from that of the classical 20S proteasome inhibitor bortezomib. In the present study, we reveal that (i) nickel pyrithione complex (NiPT) potently inhibits the UPS via targeting the 19S proteasome-associated DUBs (UCHL5 and USP14), without effecting on the 20S proteasome; (ii) NiPT selectively induces proteasome inhibition and apoptosis in cultured tumor cells and cancer cells from acute myeloid leukemia human patients; and (iii) NiPT inhibits proteasome function and tumor growth in nude mice. This study, for the first time, uncovers a nickel complex as an effective inhibitor of the 19S proteasomal DUBs and suggests a potentially new strategy for cancer treatment.

PMID:
27086925
PMCID:
PMC5497060
DOI:
10.1038/onc.2016.114
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center