Norcantharidin inhibits DNA replication and induces mitotic catastrophe by degrading initiation protein Cdc6

Chen,Sansan; Wan,Pei; Ding,Wen; Li,Fei; He,Chengwu; Chen,Pengliang; Li,Hongwei; Hu,Zhiming; Tan,Wanlong; Li,Jinlong

doi:10.3892/ijmm.2013.1359

Norcantharidin inhibits DNA replication and induces mitotic catastrophe by degrading initiation protein Cdc6

Authors:
- Sansan Chen
- Pei Wan
- Wen Ding
- Fei Li
- Chengwu He
- Pengliang Chen
- Hongwei Li
- Zhiming Hu
- Wanlong Tan
- Jinlong Li
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Affiliations: Institute of Biotherapy, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China, Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
Published online on: April 23, 2013 https://doi.org/10.3892/ijmm.2013.1359
Pages: 43-50

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Abstract

Cdc6, an essential initiation protein for DNA replication, also participates in the ATR checkpoint pathway and plays a vital role in tumorigenesis. It is involved in the androgen receptor (AR) signal transduction and promotes the malignant progression of prostate cancer (PCa). In this study, we report that norcantharidin (NCTD) induces the degradation of Cdc6 in DU145 PCa cells and as a result, the assembly of pre-replication complexes (pre-RCs) was disturbed and DNA replication was inhibited. Furthermore, treatment with NCTD blocked ATR binding to chromatin and the cells progressed into mitosis under stress induced by hydroxyurea (HU), indicating that the ATR checkpoint was evaded. Aberrant mitosis and hence, apoptosis were also observed following treatment with NCTD. Finally, NCTD exerted strong synergistic cytotoxic effects in combination with another mitotic inhibitor, paclitaxel, [combination index (CI <1)]. These data suggest that NCTD not only inhibits DNA replication but also disables the ATR-dependent checkpoint pathway by inducing Cdc6 degradation, which leads to mitotic catastrophe in DU145 cells. These findings also provide a promising prospect for the combination treatment of paclitaxel and NCTD or Cdc6 deletion in PCa.

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