Deubiquitinates (DUBs) have been suggested as novel promising targets for cancer therapies. Accumulating experimental evidence suggests that some metal compounds have the potential to induce cancer cell death via inhibition of DUBs. We previously reported that auranofin, a gold(I)-containing agent used for the treatment of rheumatoid arthritis in clinics, can induce cell death by inhibiting proteasomal DUBs in a series of cancer cell lines. Unfortunately, currently available gold compounds are not potent in inhibiting DUBs. Here, we report that: (i) aumdubin, a synthetic derivative of auranofin, exhibited stronger DUB-inhibiting and apoptosis-inducing activities than auranofin in lung cancer cells; (ii) aumdubin shows high affinity for mitochondrial DUB USP30; (iii) aumdubin induces apoptosis by increasing the ubiquitination and mitochondrial location of Bax protein; and (iv) USP30 inhibition may contribute to Bax-dependent apoptosis induced by aumdubin in lung cancer cells. These results suggest that gold(I)-containing agent aumdubin induces Bax-dependent apoptosis partly through inhibiting the mitochondrial DUB USP30, which could open new avenues for lung cancer therapy.

Deubiquitinates (DUBs) 已被建议作为新的有希望的癌症治疗靶点。越来越多的实验证据表明，一些金属化合物有可能通过抑制 DUB 来诱导癌细胞死亡。我们之前曾报道，金诺芬是一种在临床上用于治疗类风湿性关节炎的含金 (I) 药物，可通过抑制一系列癌细胞系中的蛋白酶体 DUB 来诱导细胞死亡。不幸的是，目前可用的金化合物不能有效抑制 DUB。在这里，我们报告： (i) aumdubin 是金诺芬的合成衍生物，在肺癌细胞中表现出比金诺芬更强的 DUB 抑制和细胞凋亡诱导活性；(ii) aumdubin 对线粒体 DUB USP30 显示出高亲和力；(iii) aumdubin 通过增加 Bax 蛋白的泛素化和线粒体定位来诱导细胞凋亡；(iv) USP30 抑制可能有助于肺癌细胞中 aumdubin 诱导的 Bax 依赖性细胞凋亡。这些结果表明，含金 (I) 药物 aumdubin 部分通过抑制线粒体 DUB USP30 诱导 Bax 依赖性细胞凋亡，这可能为肺癌治疗开辟新途径。