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
  • View Affiliations

  • 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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July 2013
Volume 32 Issue 1

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Chen S, Wan P, Ding W, Li F, He C, Chen P, Li H, Hu Z, Tan W, Li J, Li J, et al: Norcantharidin inhibits DNA replication and induces mitotic catastrophe by degrading initiation protein Cdc6. Int J Mol Med 32: 43-50, 2013
APA
Chen, S., Wan, P., Ding, W., Li, F., He, C., Chen, P. ... Li, J. (2013). Norcantharidin inhibits DNA replication and induces mitotic catastrophe by degrading initiation protein Cdc6. International Journal of Molecular Medicine, 32, 43-50. https://doi.org/10.3892/ijmm.2013.1359
MLA
Chen, S., Wan, P., Ding, W., Li, F., He, C., Chen, P., Li, H., Hu, Z., Tan, W., Li, J."Norcantharidin inhibits DNA replication and induces mitotic catastrophe by degrading initiation protein Cdc6". International Journal of Molecular Medicine 32.1 (2013): 43-50.
Chicago
Chen, S., Wan, P., Ding, W., Li, F., He, C., Chen, P., Li, H., Hu, Z., Tan, W., Li, J."Norcantharidin inhibits DNA replication and induces mitotic catastrophe by degrading initiation protein Cdc6". International Journal of Molecular Medicine 32, no. 1 (2013): 43-50. https://doi.org/10.3892/ijmm.2013.1359