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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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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