Yan Ding, Li Xiaofen, Yang Qianqian, Huang Qingtian, Yao Leyi, Zhang Peiquan, Sun Wenshuang, Lin Shuhui, Dou Q Ping, Liu Jinbao, Chen Xin
Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, China.
Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
Cell Death Discov. 2021 Aug 11;7(1):211. doi: 10.1038/s41420-021-00599-6.
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.
去泛素化酶（DUBs）已被认为是癌症治疗中颇具前景的新型靶点。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DUBs诱导癌细胞死亡。我们之前报道过，金诺芬，一种临床上用于治疗类风湿性关节炎的含金（I）制剂，可通过抑制一系列癌细胞系中的蛋白酶体DUBs诱导细胞死亡。不幸的是，目前可用的金化合物在抑制DUBs方面效果不佳。在此，我们报道：（i）金诺芬的合成衍生物奥姆杜宾在肺癌细胞中表现出比金诺芬更强的DUB抑制和凋亡诱导活性；（ii）奥姆杜宾对线粒体DUB USP30具有高亲和力；（iii）奥姆杜宾通过增加Bax蛋白的泛素化和线粒体定位诱导凋亡；（iv）USP30抑制可能有助于奥姆杜宾在肺癌细胞中诱导的Bax依赖性凋亡。这些结果表明，含金（I）制剂奥姆杜宾部分通过抑制线粒体DUB USP30诱导Bax依赖性凋亡，这可能为肺癌治疗开辟新途径。
