Signal transducers and activators of transcription 3 pathway activation in drug-resistant ovarian cancer
Signal transducers and activators of transcription 3 pathway activation in drug-resistant ovarian cancer
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DOI：
10.1158/1078-0432.ccr-06-0861
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发表时间：
2006-09-01
影响因子：
11.5
通讯作者：
Seiden, Michael V.
中科院分区：
文献类型：
--
作者：
Duan, Zhenfeng;Foster, Rosemary;Seiden, Michael V.
目的：卵巢癌治疗的主要障碍之一是多药耐药的产生。最近的证据表明，高级别卵巢癌通常表现为信号转导和转录激活因子3(STAT3)途径的激活，随后转录支持肿瘤生长和生存的基因。STAT3通路在获得性耐药中的作用研究较少。为了进一步阐明STAT3激活在卵巢癌中的意义，我们研究了STAT3在卵巢癌和卵巢癌多药耐药细胞系中的表达和激活，实验设计：Western blotting、凝胶迁移率改变分析、荧光素酶分析、ELISA法和实时逆转录-聚合酶链式反应(Real-Time RT-PCR)检测细胞系中IL-6和STAT3通路的表达和激活。结果：活化(磷酸化)的STAT3在大多数紫杉醇耐药的卵巢癌细胞中高表达。抑制STAT3的激活可显著降低紫杉醇的耐药性，促进细胞凋亡。与匹配的原发肿瘤相比，耐药复发肿瘤的磷酸化STAT3(PStat3)的表达显著增加。与无炎性细胞浸润者相比，伴有炎性细胞浸润的肿瘤细胞中有更多的细胞表达核磷酸化的STAT3，这与免疫介导的细胞因子通过旁分泌激活STAT3途径相一致。结论：这些数据支持阻断STAT3信号转导可以逆转对紫杉醇等化疗药物的耐药性。
Purpose: One of the major obstacles in the treatment of ovarian cancer is the development of multidrug resistance. Recent evidence shows that high-grade ovarian cancer often shows activation of the signal transducers and activators of transcription 3 (Stat3) pathway with subsequent transcription of genes that support tumor growth and survival. Less studied is the role of the Stat3 pathway in acquired drug resistance. There is no information on Stat3 expression in chemotherapy naive ovarian cancer as compared with tumors collected later in the natural history of the disease, To further clarify the significance of Stat3 activation in ovarian cancer, here we investigated the Stat3 expression and activation in ovarian cancer and ovarian cancer multidrug resistance cell lines,Experimental Design: Western blotting, electrophoretic mobility shift assay, luciferase assays, ELISA assay, and real-time reverse transcription-PCR determined interleukin-6 and Stat3 pathway expression and activation in cell lines. Stat3 expression in ovarian cancer tissue microarray was evaluated by immunohistochemistry.Results: Activated (phosphorylated) Stat3 is overexpressed in most paclitaxel-resistant ovarian cancer cells. Inhibition of Stat3 activation results in significant decreases in paclitaxel resistance and enhanced apoptosis. Drug-resistant recurrent tumors have significantly greater phosphorylated Stat3 (pStat3) expression as compared with matched primary tumors. Tumors with associated inflammatory cell infiltrates also have a higher proportion of cells staining intensely for nuclear phosphorylated Stat3 as compared with tumors without inflammatory infiltrates, consistent with paracrine activation of the Stat3 pathway by immune-mediated cytokines.Conclusions: These data support the hypothesis that interruption of Stat3 signaling could reverse resistance to paclitaxel and perhaps other chemotherapy agents in human cancer.