卵巢癌中E2通过ERα降低顺铂敏感性的研究-东南大学学报医学版

卵巢癌中E2通过ERα降低顺铂敏感性的研究

单位：1. 长治医学院药学系, 山西长治 046000;
2. 中国人民解放军火箭军总医院, 北京 100032

分类号：R737.31

出版年·卷·期（页码）：2017·36·第三期（422-428）

摘要：

目的：探讨顺铂治疗的卵巢癌中铂抵抗与雌激素受体（ERα）及17β-雌二醇（E2）之间的关系。方法：以卵巢癌细胞系Caov-3和Ovcar-3作为研究模型，分别给予不同药物处理，并设计ERα-siRNA对ERα进行下调，研究在不同处理方式下卵巢癌细胞的增殖及凋亡水平，同时分析顺铂对ERα磷酸化、蛋白激酶B （Akt）和细胞外信号调节蛋白激酶（ERK）的调节。结果：在卵巢癌细胞中，E2通过ERα促进细胞增殖，并降低卵巢癌细胞对顺铂的敏感性；ER拮抗剂ICI 182780（ICI）可以增强卵巢癌细胞对顺铂的敏感性；顺铂通过激活ERK诱导ERα的磷酸化，其磷酸化位点为丝氨酸118；下调ERα后，E2对顺铂细胞毒性的拮抗作用降低，且经E2处理后，卵巢癌细胞的抗凋亡蛋白Bcl-2表达上调，细胞的凋亡降低。结论：卵巢癌中，ERα在顺铂抵抗中扮演重要角色，E2通过诱导ERα激活并降低凋亡，进而降低顺铂的细胞毒性。因此在铂抗性卵巢癌的治疗中，ERα可能是一个潜在的治疗靶标。

Objective:To investigate the relationship among platinum resistance, estrogen receptor alpha(ERα)and 17β-estradiol(E2)in ovarian carcinoma treated with cisplatin. Methods:The ovarian cancer cell lines Caov-3 and Ovcar-3 were treated with different drugs. ERα-siRNA was designed to down-regulate the expression of ERα in ovarian cancer cell lines. Apoptosis and growth of ovarian cancer cells were detected. Moreover, the regulations of ERα phosphorylation, protein kinase B(Akt)and extracellular signal regulated kinase(ERK)by cisplatin were measured. Results:In ovarian cancer cells, E2 promoted cell proliferation through ERα and decreased the sensitivity of ovarian cancer cells to cisplatin. ER antagonist ICI 182780(ICI)enhanced the sensitivity of ovarian cancer cells to cisplatin,cisplatin activated ERK phosphorylation by the regulations of ERK, and the phosphorylation site of ERα was at serine 118. After the down-regulation of ERα, the antagonistic effect of E2 on the cytotoxicity of cisplatin was decreased. After treatment with E2, the anti-apoptotic protein Bcl-2 of ovarian cancer cells was up-regulated, and the cell apoptosis decreased. Conclusion:ERα plays an important role in the resistance to cisplatin in ovarian cancer treatment. E2 can decrease the cisplatin cytotoxicity by inducing ERα activation and decreasing apoptosis. Therefore, ERα may be a potential therapeutic target in the treatment of platinum-resistant ovarian cancer.

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