title: A novel nickel complex works as a proteasomal deubiquitinase inhibitor for cancer therapy.
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.
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangzhou, China.
authors.forename: C
authors.initials: C
authors.lastname: Zhao
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangzhou, China.
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangzhou, China.
authors.forename: D
authors.initials: D
authors.lastname: Zang
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangzhou, China.
authors.forename: X
authors.initials: X
authors.lastname: Lan
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangzhou, China.
authors.forename: S
authors.initials: S
authors.lastname: Liao
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangzhou, China.
authors.forename: C
authors.initials: C
authors.lastname: Yang
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangzhou, China.
authors.forename: P
authors.initials: P
authors.lastname: Zhang
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangzhou, China.
authors.forename: J
authors.initials: J
authors.lastname: Wu
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangzhou, China.
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangzhou, China.|Guangzhou Research Institute of Cardiovascular Disease, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
authors.forename: N
authors.initials: N
authors.lastname: Liu
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangzhou, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liao
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangzhou, China.
authors.forename: H
authors.initials: H
authors.lastname: Huang
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangzhou, China.
authors.forename: X
authors.initials: X
authors.lastname: Shi
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangzhou, China.
authors.forename: L
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Institute of Environmental and Analytical Sciences, College of Chemistry and Chemical Engineering, Henan University, Kaifeng, China.|Key Lab of Natural Drug and Immune Engineering of Henan Province, Kaifeng, China.
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.affiliation: Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, China.
authors.forename: Z
authors.initials: Z
authors.lastname: He
authors.affiliation: The Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.|Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, MI, USA.
authors.forename: Q P
authors.initials: QP
authors.lastname: Dou
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangzhou, China.|Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, SD, USA.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangzhou, China.
authors.forename: J
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D009532:Nickel / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D025801:Ubiquitin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D061988:Proteasome Inhibitors; D025801:Ubiquitin; D009532:Nickel; D046988:Proteasome Endopeptidase Complex