Article

Mebendazole elicits potent antimyeloma activity by inhibiting the USP5/c-Maf axis

Authors: Xue-han Chen1, Yu-jia Xu1, Xiao-ge Wang2, Peng Lin1, Bi-yin Cao1, Yuan-ying Zeng3, Qi Wang2, Zu-bin Zhang1, Xin-liang Mao1,2, Tie Zhang4
1 Jiangsu Key Laboratory of Neuropsychiatric Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China
2 Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
3 Department of Oncology, Suzhou Municipal Hospital, Suzhou 215100, China
4 Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
Correspondence to: Zu-bin Zhang: zhangzubin@suda.edu.cn, Xin-liang Mao: xinliangmao@suda.edu.cn, Tie Zhang: zhangtieaa@sina.com.cn,
DOI: 10.1038/s41401-019-0249-1
Received: 22 February 2019
Accepted: 8 May 2019
Advance online: 13 June 2019

Abstract

c-Maf is a critical oncogenic transcription factor that contributes to myelomagenesis. Our previous studies demonstrated that the deubiquitinase USP5 stabilizes c-Maf and promotes myeloma cell proliferation and survival; therefore, the USP5/c-Maf axis could be a potential target for myeloma therapy. As a concept of principle, the present study established a USP5/c-Maf-based luciferase system that was used to screen an FDA-approved drug library. It was found that mebendazole, a typical anthelmintic drug, preferentially induced apoptosis in c-Maf-expressing myeloma cells. Moreover, oral administration of mebendazole delayed the growth of human myeloma xenografts in nude mice but did not show overt toxicity. Further studies showed that the selective antimyeloma activity of mebendazole was associated with the inhibition of the USP5/c-Maf axis. Mebendazole downregulated USP5 expression and disrupted the interaction between USP5 and c-Maf, thus leading to increased levels of c-Maf ubiquitination and subsequent c-Maf degradation. Mebendazole inhibited c-Maf transcriptional activity, as confirmed by both luciferase assays and expression measurements of c-Maf downstream genes. In summary, this study identified mebendazole as a USP5/c-Maf inhibitor that could be developed as a novel antimyeloma agent.
Keywords: c-Maf; USP5; mebendazole; multiple myeloma; ubiquitination

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