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

Oncogene volume 35, pages 5916–5927 (2016)Cite this article

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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.

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Acknowledgements

We thank Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital and Sun Yat-Sen University for flow cytometry detection. This work was supported by the National High Technology Research and Development Program of China (2006AA02Z4B5), NSFC (81272451/H1609, 81472762/H1609), MOE (20134423110002) and Guangdong Key Laboratory of Urology (2010A060801016) (to JL) and in part by US NIH grants HL072166 and HL085629 (to XW).

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Author notes

  1. C Zhao and X Chen: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathophysiology, State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Guangzhou Medical University, Guangzhou, China

    C Zhao, X Chen, D Zang, X Lan, S Liao, C Yang, P Zhang, J Wu, X Li, N Liu, Y Liao, H Huang, X Shi, L Jiang, X Wang & J Liu

  2. Guangzhou Research Institute of Cardiovascular Disease, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China

    N Liu

  3. Institute of Environmental and Analytical Sciences, College of Chemistry and Chemical Engineering, Henan University, Kaifeng, China

    X Liu

  4. Key Lab of Natural Drug and Immune Engineering of Henan Province, Kaifeng, China

    X Liu

  5. Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, China

    Z He

  6. The Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA

    Q P Dou

  7. Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, MI, USA

    Q P Dou

  8. Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, SD, USA

    X Wang

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Correspondence to J Liu.

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Zhao, C., Chen, X., Zang, D. et al. A novel nickel complex works as a proteasomal deubiquitinase inhibitor for cancer therapy. Oncogene 35, 5916–5927 (2016). https://doi.org/10.1038/onc.2016.114

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  • DOI: https://doi.org/10.1038/onc.2016.114

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