Niclosamide exerts anticancer effects through inhibition of the FOXM1-mediated DNA damage response in prostate cancer |
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Authors: | Mee Young Kim Ae Ryang Jung Dongho Shin Hyeokjae Kwon Hyuk Jin Cho U-Syn Ha Sung-Hoo Hong Ji Youl Lee Sae Woong Kim Yong Hyun Park |
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Affiliation: | 1. Department of Urology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea ; 2. Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea |
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Abstract: | Niclosamide, an established anti-helminthic drug, has anticancer activity against various cancers including prostate cancer, but the underlying mechanisms have not yet been defined. We demonstrated the anticancer effects of niclosamide in castration-resistant prostate cancer (CRPC) cells, and elucidated the mechanism of action of niclosamide in CRPC. Niclosamide reduced cell proliferation and induced apoptosis of CRPC cells in vitro, and also reduced xenograft tumor growth in vivo. Niclosamide significantly increased the number of γH2AX- and 53BP1-positive cells. In RNA-sequencing, niclosamide induced extensive changes in gene expression including cell division, DNA replication, and DNA repair. Bioinformatics analysis using TCGA data set revealed that FOXM1 is an important target of niclosamide. In microarray assays, FOXM1 knockdown significantly inhibited several genes involved in DNA repair, and homologous recombination, in particular. Finally, FOXM1 strongly bound to EXO1 in CRPC cells, and FOXM1 knockdown significantly reduced EXO1-driven luciferase activity. Taken together, our results suggest that niclosamide exerts anticancer activity through inhibition of the FOXM1-mediated DNA damage response in CRPC. |
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Keywords: | Castration-resistant prostate cancer niclosamide FOXM1 EXO1 DNA damage response |
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