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.

Nickel pyrithione induces apoptosis in chronic myeloid leukemia cells resistant to imatinib via both Bcr/Abl-dependent and Bcr/Abl-independent mechanisms

“…Like in other cancer cells, we previously reported [27], we found that NiPT dose- and time-dependently induced accumulation of ubiquitinated proteins (Ubs) and proteasome substrate protein p27 in all CML cell lines we detected before the emergence of PARP cleavage (Fig. 3a).…”

“…As displayed in Fig. 5a, NiPT decreased the cell viability of primary monocytes from CML patients with IC 50 values ranging from 0.58 to 0.82 μM, while for the peripheral mononuclear cells from three healthy volunteers the IC 50 values were more than 3.0 μM as we reported recently [27].

Fig.

…”

“…Recently, we have reported that NiPT is able to inhibit the activity of 19S proteasome-associated DUBs USP14 and UCHL5 but not the 20S proteasome [27]. We confirmed that NiPT induces cell apoptosis and overcomes IM-resistance in CML cells through both Bcr-Abl-dependent and Bcr-Abl-independent mechanisms.…”

“…Previously, we have reported that NiPT could produce tumor tissue-specific proteasome-associated DUBs inhibition and tumor-specific toxicity, which might have clinical significance for designing novel strategies for cancer treatment [27]. In this study, we analyzed the mechanism of action of NiPT, the nickel ion, and PT-chelating product with previously reported inhibitory activity of 19S proteasome-associated DUBs, in overcoming IM-resistant CML cells in vitro, ex vivo and in vivo.…”

“…Pyrithione (PT) possesses well-defined metal-chelating properties, and the zinc complex of pyrithione (ZnPT) was found to exert significant anti-cancer effects [26]. And only recently we have definitely confirmed that nickel pyrithione (NiPT) inhibits the 19S proteasome-associated deubiquitinases (DUBs) USP14 and UCHL5, but not the 20S proteasome peptidases, and the inhibition of proteasome-associated DUBs induces NiPT-mediated cytotoxicity, revealing a novel mechanism for the anti-cancer effects of nickel-containing compounds [27]. Although proteasome inhibitors such as bortezomib (PS-341) and gambogic acid (GA) have been reported to downregulate or inhibit Bcr-Abl expression and induce cell apoptosis in CML cells [28, 29], the role of DUB inhibitors, especially inhibitors of the 19S proteasome-associated DUBs, in Bcr-Abl hematopoietic malignancies remains unknown.…”