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.
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Acknowledgements
This work was partly supported by the National Natural Science Foundation of China (81320108023 to XM, 81600171 to ZZ, and 81770215 to BC), the Natural Science Foundation of Jiangsu Higher Education Institutes of China (17KJA180010 to XM), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD to XM), and the Jiangsu Key Laboratory for Neuro-Psycho-Diseases (BK2013003 to XM). The study was also partly supported by the Suzhou Key Laboratory for Pediatric Leukemia (SZS201615 to XM) and the Suzhou Key Medical Center (Szzx201506 to YZ).
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XM, ZZ, and TZ designed the study; XC, YX, XW, ZZ, PL, and BC conducted the experiments; XM, XC, YZ, QW, and TZ analyzed the data; and XM and XC wrote the manuscript.
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Chen, Xh., Xu, Yj., Wang, Xg. et al. Mebendazole elicits potent antimyeloma activity by inhibiting the USP5/c-Maf axis. Acta Pharmacol Sin 40, 1568–1577 (2019). https://doi.org/10.1038/s41401-019-0249-1
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DOI: https://doi.org/10.1038/s41401-019-0249-1
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