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Niclosamide exerts anticancer effects through inhibition of the FOXM1-mediated DNA damage response in prostate cancer.

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.

SUBMITTER: Kim MY

PROVIDER: S-EPMC8263667 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Niclosamide exerts anticancer effects through inhibition of the FOXM1-mediated DNA damage response in prostate cancer.

Kim Mee Young MY Jung Ae Ryang AR Shin Dongho D Kwon Hyeokjae H Cho Hyuk Jin HJ Ha U-Syn US Hong Sung-Hoo SH Lee Ji Youl JY Kim Sae Woong SW Park Yong Hyun YH

American journal of cancer research 20210615 6

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 <i>in vitro</i>, and also reduced xenograft tumor growth <i>in vivo</i>. ...[more]

PMID: 34249437

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Project description:Introduction: Forkhead (FOX) transcription factors are involved in cell cycle control, cellular differentiation, maintenance of tissues, and aging. Mutation or aberrant expression of FOX proteins is associated with developmental disorders and cancers. FOXM1, an oncogenic transcription factor, is a promoter of cell proliferation and accelerated development of breast adenocarcinomas, squamous carcinoma of the head, neck, and cervix, and nasopharyngeal carcinoma. High FOXM1 expression is correlated with chemoresistance in patients treated with doxorubicin and Epirubicin by enhancing the DNA repair in breast cancer cells. Method: miRNA-seq identified downregulation of miR-4521 in breast cancer cell lines. Stable miR-4521 overexpressing breast cancer cell lines (MCF-7, MDA-MB-468) were developed to identify miR-4521 target gene and function in breast cancer. Results: Here, we showed that FOXM1 is a direct target of miR-4521 in breast cancer. Overexpression of miR-4521 significantly downregulated FOXM1 expression in breast cancer cells. FOXM1 regulates cell cycle progression and DNA damage response in breast cancer. We showed that miR-4521 expression leads to increased ROS levels and DNA damage in breast cancer cells. FOXM1 plays a critical role in ROS scavenging and promotes stemness which contributes to drug resistance in breast cancer. We observed that breast cancer cells stably expressing miR-4521 lead to cell cycle arrest, impaired FOXM1 mediated DNA damage response leading to increased cell death in breast cancer cells. Additionally, miR-4521-mediated FOXM1 downregulation perturbs cell proliferation, invasion, cell cycle progression, and epithelial-to-mesenchymal progression (EMT) in breast cancer. Discussion: High FOXM1 expression has been associated with radio and chemoresistance contributing to poor patient survival in multiple cancers, including breast cancer. Our study showed that FOXM1 mediated DNA damage response could be targeted using miR-4521 mimics as a novel therapeutic for breast cancer.

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Niclosamide exerts anticancer effects through inhibition of the FOXM1-mediated DNA damage response in prostate cancer.

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Niclosamide exerts anticancer effects through inhibition of the FOXM1-mediated DNA damage response in prostate cancer.

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