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

Cyclin A 通过激活 PI-3K 通路赋予子宫内膜癌细胞 CDDP 抗性

基本信息

批准号：
17591726
负责人：
KATO Kiyoshi
金额：
$ 2.24万
依托单位：
SHINSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591726/
关键词：
cyclin A apoptosis chemoresistanse Endometrial carcinoma periplakin chemotherapy PI3-kinase pathway MAP kinase

项目摘要

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.

我们的这项研究的目的是检查子宫内膜癌中的cyclina过表达的假说可能会影响子宫内膜钙NIMA细胞的生长以及对抗癌药物的敏感性。为了获得这一假设，我们首先建立了一种稳定的细胞周期蛋白，一种表达子宫内膜癌细胞系（Cyc A HUA），这表明了一种越来越多的活性，这表明了一种替代性的动物，并延伸了对化学量的影响。我们还观察到，暴露于抗癌药物后的抑制增加，伴随着凋亡的降低。以下免疫印迹研究表明，抗性的部分原因是抗凋亡因子的表达增加，Bcl-2以及促凋亡因子的失活不好。然后，我们评估了PI3K-AKT抗凋亡途径的参与。 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 Cyclina的抗凋亡作用。分析表明，Akt结合蛋白Periplakin（PPL）在CYC A HHUA中被上调。免疫沉淀表明，PPL的AKT结合部分也增加了Cyclin A的表达A. PPL特异性siRNA的转染成功降低了Akt磷酸化，这表明PPL与Akt的结合表明PI3K-AKT途径的稳定性使PI3K-AKT途径信号转向。子宫内膜癌细胞中的CDDP耐药性，并且该作用是通过PPL稳定AKT途径介导的。