Cyclin I promotes cisplatin resistance via Cdk5 activation in cervical cancer.

ABSTRACT

OBJECTIVE: Cisplatin (cis-diamminedichloroplatinum II, CDDP) is one of the most effective chemotherapeutic agents and is widely used in the treatment of cervical cancer (CC), but cancer cell acquired resistance to this drug during the course of its treatment. The aim of this study was to investigate the role of cyclin I to cisplatin resistance in CC cell. PATIENTS AND METHODS: Cervical tumor specimens from 30 patients were recruited in this study. We analyzed the expression of cyclin I by real-time polymerase chain reaction (qRT-PCR), Western blotting examination of downstream effectors. Cell proliferation assay and xenograft experiments were performed for cisplatin cytotoxicity assay. Lentivirus-mediated and siRNA-mediated genes overexpression or knockdown were applied to investigate the role of cyclin I to cisplatin resistance in CC cell. RESULTS: We found that high level of cyclin I was associated with cisplatin resistance in CC. Here, we described that cyclin I protein becomes highly expressed in human CC patients resistant to cisplatin chemotherapy. Stable overexpressed cyclin I promotes Hela cell resistance to higher concentrations of cisplatin. In addition, upregulated level of cyclin I increased tumor cells growth in vitro and enhanced tumor resistance to cisplatin in vivo. The further mechanism investigated showed that cyclin I upregulated the expression of cyclin-dependent kinase 5 (Cdk5) promoting cisplatin resistance by preventing apoptosis in CC cell line. Consistently, the cyclin I overexpressed Hela cell lines produce increased sensitivity to cisplatin treatment through knockdown of Cdk5 protein with siRNA. CONCLUSIONS: These data suggest that a cyclin I-Cdk5 complex forms a critical antiapoptotic factor in the process of generating cisplatin resistance in cervical cancer.