Norcantharidin inhibits DNA replication and induces mitotic catastrophe by degrading initiation protein Cdc6.
Int J Mol Med
; 32(1): 43-50, 2013 Jul.
Article
en En
| MEDLINE
| ID: mdl-23612688
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Proteínas Nucleares
/
Proteínas de Ciclo Celular
/
Compuestos Bicíclicos Heterocíclicos con Puentes
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Replicación del ADN
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Mitosis
Límite:
Humans
Idioma:
En
Revista:
Int J Mol Med
Asunto de la revista:
BIOLOGIA MOLECULAR
/
GENETICA MEDICA
Año:
2013
Tipo del documento:
Article