Suppression of ovarian cancer cell tumorigenicity and evasion of cisplatin resistance using a truncated epidermal growth factor receptor in a rat model
Suppression of ovarian cancer cell tumorigenicity and evasion of cisplatin resistance using a truncated epidermal growth factor receptor in a rat model
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DOI：
10.1158/0008-5472.can-03-3013
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发表时间：
2005-04-15
期刊：
影响因子：
11.2
通讯作者：
Fan, H
中科院分区：
文献类型：
--
作者：
Chan, JK;Pham, HY;Fan, H
表皮生长因子受体（EGFR）的过度表达与卵巢癌的预后不良有关。显性负性FGFR（EGFR-DNR）是缺乏酪氨酸激酶结构域并且缺乏信号传导能力的截短受体。这项研究测试了EGFR-DNR方法在卵巢癌细胞中的作用。使大鼠卵巢癌细胞系NuTu-19对顺铂产生耐药性。用含有EGFR-DNTR的逆转录病毒载体感染NuTu-19和抗性细胞。将NuTu-19和NuTu-DNR（表达EGFR-DNR的NuTu-19细胞）注射到Fisher 344免疫活性大鼠中。Western印迹分析用于评估信号转导途径。所有注射NuTu-DNR细胞的大鼠在肿瘤注射后保持健康。相比之下，注射NuTu-19和NuTu-Sham（表达空载体的NuTu-19细胞）的大鼠在15周结束时100%死于疾病进展（P = 0.00009）。在Western印迹分析中，NuTu-19和NuTu-Sham细胞暴露于FGF后均显示出丝裂原活化蛋白激酶（MAPK）的强烈活化。顺铂耐药细胞系通过MAPK途径表现出增强的EGF刺激作用与亲本细胞相比。EGFR-DNR显著降低EGF通过MAPK途径诱导细胞信号传导的能力。最后，EGFR-DNR可以部分逆转耐药细胞的顺铂耐药性。EGFR-DNR方法表明EGFR在体内赋予NuTu-19细胞生长优势。因此，EGFR阻断可能最终被证明是治疗顺铂敏感和顺铂耐药卵巢癌的有用治疗工具。
The overexpression of the epidermal growth factor receptor (EGFR) is associated with a poor prognosis in ovarian cancer. The dominant-negative FGFR (EGFR-DNR) is a truncated receptor that lacks the tyrosine kinase domain and is devoid of signaling capability. This study tested the effects of a EGFR-DNR approach in ovarian cancer cells. NuTu-19, a rat ovarian cancer cell line was rendered resistant to cisplatin. Both NuTu-19 and resistant cells were infected with a retroviral vector containing the EGFR-DNTR. NuTu-19 and NuTu-DNR (NuTu-19 cells expressing the EGFR-DNR) were injected into Fisher 344 immunocompetent rats. Western blot analyses were used to assess signal transduction pathways. All rats injected with NuTu-DNR cells remained healthy following tumor injection. In contrast, 100% of the rats injected with the NuTu-19 and NuTu-Sham (NuTu-19 cells expressing an empty vector) died of disease progression at the end of 15 weeks (P = 0.00009). On Western blot analysis, both NuTu-19 and NuTu-Sham cells showed a strong activation of mitogen-activated protein kinase (MAPK) after exposure to FGF. Cisplatin-resistant cell lines showed an enhanced EGF stimulatory effect via the MAPK pathway compared with parental cells. The EGFR-DNR significantly reduced the ability of EGF to induce cell signaling through the MAPK pathway. Lastly, the EGFR-DNR can partially reverse cisplatin resistance in drug-resistant cells. The EGFR-DNR approach suggests that EGFR confers a growth advantage to NuTu-19 cells in vivo. Thus, EGFR blockade may ultimately prove to be a useful therapeutic tool in the treatment of cisplatin-sensitive and cisplatin-resistant ovarian cancers.