Cyclin A confers CDDP resistance to endometrial carcinoma cells via activation of PI-3K pathway

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Our objective of this study was to examine the hypothesis that the cyclinA overexpression in endometrial cancer may influence the growth of the endometrial caricnima cell as well as the sensitivity to anticancer drugs.To access this hypothesis, we first established a stable cyclin A expressing endometrial carcinoma cell line (cyc A HHUA), which demonstrated an increased proliferative activity and resistance to chemotherapeutic agents. We also observed that the increased resistance was accompanied with reduced apoptosis after the exposure to anticancer drugs. The following immunoblotting study revealed that the resistance was in part due to the increased expressions of antiapoptotic factor, Bcl-2 as well as the inactivation of proapoptotic factor, Bad. We then evaluated the involvement of PI3K-Akt antiapoptotic pathway. Activating phosphorylation was augmented after the exposure to CDDP in cyc A HHUA compared with the control, suggesting that the PI-3K pathway plays an important role in cyclinA-induced CDDP resistance.To further examine the mechanisms of cyclin A-induced CDCP resistance, we performed an oligonucleotide array analysis between the cycA HHUA and control HHUA to identify new molecules involved in the antiapoptotic effects of cyclinA. The analysis revealed that an Akt-binding protein, periplakin (PPL), was up-regulated in cyc A HHUA. Immunoprecipitation showed that the Akt-binding fraction of PPL was also increased along with the increased expression of cyclin A. Transfection of PPL-specific siRNA successfully reduced Akt phosphorylation, indicating that the binding of PPL to Akt stabilized the PI3K-Akt pathway signaling.In conclusion, we have newly revealed that the cyclin A exerted an antiapoptotic effect repoponsible for CDDP resistance in endometrial cancer cells, and that the effect was mediated via the stabilization of Akt pathway by PPL.