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

• 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

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.

本研究的目的是验证周期蛋白A在子宫内膜癌中过表达可能影响子宫内膜癌细胞的生长以及对抗癌药物的敏感性的假说。为了验证这一假说，我们首先建立了稳定表达周期蛋白A的子宫内膜癌细胞系(Cyc A HHUA)，该细胞系表现出更强的增殖活性和对化疗药物的耐药性。我们还观察到，在接触抗癌药物后，耐药性的增加伴随着细胞凋亡的减少。随后的免疫印迹研究表明，耐药的部分原因是抗凋亡因子Bcl2的表达增加以及促凋亡因子Bad的失活。然后，我们评估了PI3K-Akt抗凋亡通路的参与。与对照组相比，细胞周期蛋白A HHUA的活化磷酸化增强，表明PI-3K通路在细胞周期蛋白A诱导的CDDP耐药中起重要作用。为了进一步研究细胞周期蛋白A诱导CDCP耐药的机制，我们在细胞周期蛋白A和对照细胞之间进行了寡核苷酸阵列分析，以寻找参与细胞周期蛋白A抗细胞凋亡作用的新分子。分析表明，Akt结合蛋白PPL在Cyc A HHUA中表达上调。免疫沉淀结果显示，随着细胞周期蛋白A表达的增加，PPL的Akt结合比例也随之增加。转染PPL特异的siRNA成功地降低了Akt的磷酸化，表明PPL与Akt的结合稳定了PI3K-Akt信号通路。综上所述，我们新发现了细胞周期蛋白A对CDDP耐药的子宫内膜癌细胞具有抗凋亡作用，该作用是通过PPL稳定Akt途径实现的。

项目成果

BRAF mutation in endometrial carcinoma and hyperplasia:: Correlation with KRAS and p53 mutations and mismatch repair protein expression

• DOI: 10.1158/1078-0432.ccr-04-2670
• 发表时间: 2005-09-01
• 期刊: CLINICAL CANCER RESEARCH
• 影响因子: 11.5
• 作者: Feng, YZ;Shiozawa, T;Konishi, I
• 通讯作者: Konishi, I

Overexpression of hedgehog signaling molecules and its involvement in the proliferation of endometrial carcinoma cells

• DOI: 10.1158/1078-0432.ccr-06-1407
• 发表时间: 2007-03-01
• 期刊: CLINICAL CANCER RESEARCH
• 影响因子: 11.5
• 作者: Feng, Yu-Zhen;Shiozawa, Tanri;Konishi, Ikuo
• 通讯作者: Konishi, Ikuo

Leiomyoma of the ovary presenting with Meigs' syndrome

• DOI: 10.1111/j.1447-0756.2005.00285.x
• 发表时间: 2005-01-01
• 期刊: JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH
• 影响因子: 1.6
• 作者: Kurai, M;Shiozawa, T;Konishi, I
• 通讯作者: Konishi, I

Intratumoral heterogeneous expression of p53 correlates with p53 mutation, Ki-67, and cyclin A expression in endometrioid-type endometrial adenocarcinomas

• DOI: 10.1007/s00428-005-0029-9
• 发表时间: 2005-07
• 期刊: Virchows Archiv
• 影响因子: 3.5
• 作者: Yuzhen Feng;T. Shiozawa;A. Horiuchi;Hsien-Chang Shih;T. Miyamoto;H. Kashima;A. Suzuki;T. Nikaido;I. Konishi

Cystic clear cell tumor of borderline malignancy of the ovary lacking fibromatous components : Report of two cases and a possible new histological subtype.

缺乏纤维瘤成分的卵巢交界性恶性肿瘤的囊性透明细胞瘤：两例报告和可能的新组织学亚型。

• 发表时间: 2006
• 期刊: Gynecol Oncol 101
• 作者: Suzuki A;Shiozawa T;Mori A;Kimura K;Konishi I
• 通讯作者: Konishi I