A novel nickel complex works as a proteasomal deubiquitinase inhibitor for cancer therapy.
A novel nickel complex works as a proteasomal deubiquitinase inhibitor for cancer therapy.
复制标题
一种新型镍络合物作为蛋白酶体去泛素酶抑制剂用于癌症治疗
作者：
Zhao C;Chen X;Zang D;Lan X;Liao S;Yang C;Zhang P;Wu J;Li X;Liu N;Liao Y;Huang H;Shi X;Jiang L;Liu X;He Z;Dou QP;Wang X;Liu J
基于泛素-蛋白酶体系统（UPS）在细胞蛋白降解中的中心作用，蛋白酶体抑制剂已被认为是一种有吸引力的抗癌治疗方法。去泛素化酶（DUBs）从不同的底物中去除泛素结合物;因此，它们是UPS的重要调节剂。DUB抑制剂，尤其是蛋白酶体DUB抑制剂，正成为肿瘤靶向治疗的研究热点。已有研究表明，铜、锌等金属配合物可通过抑制UPS功能诱导肿瘤细胞凋亡。此外，我们已经发现，铜pyrimidine抑制19 S蛋白酶体相关DUBs和20 S蛋白酶体活性的机制不同于经典的20 S蛋白酶体抑制剂硼替佐米。在本研究中，我们揭示了（i）吡啶硫酮镍复合物（NiPT）通过靶向19 S蛋白酶体相关DUB有效抑制UPS（ii）NiPT选择性地诱导来自急性髓性白血病人患者的培养的肿瘤细胞和癌细胞中的蛋白酶体抑制和细胞凋亡;和（iii）NiPT抑制裸鼠中的蛋白酶体功能和肿瘤生长。这项研究首次揭示了镍络合物作为19 S蛋白酶体DUBs的有效抑制剂，并提出了一种潜在的癌症治疗新策略。
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.