期刊
ACTA PHARMACOLOGICA SINICA
卷 40, 期 12, 页码 1568-1577出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41401-019-0249-1
关键词
c-Maf; USP5; mebendazole; multiple myeloma; ubiquitination
资金
- National Natural Science Foundation of China [81320108023, 81600171, 81770215]
- Natural Science Foundation of Jiangsu Higher Education Institutes of China [17KJA180010]
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
- Jiangsu Key Laboratory for Neuro-Psycho-Diseases [BK2013003]
- Suzhou Key Laboratory for Pediatric Leukemia [SZS201615]
- Suzhou Key Medical Center [Szzx201506]
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.
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