APE1 overexpression is associated with cisplatin resistance in non-small cell lung cancer and targeted inhibition of APE1 enhances the activity of cisplatin in A549 cells
APE1 overexpression is associated with cisplatin resistance in non-small cell lung cancer and targeted inhibition of APE1 enhances the activity of cisplatin in A549 cells
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DOI：
10.1016/j.lungcan.2009.02.019
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发表时间：
2009-12-01
期刊：
影响因子：
5.3
通讯作者：
Zhang, Yun-Song
中科院分区：
文献类型：
--
作者：
Wang, Dong;Xiang, De-Bing;Zhang, Yun-Song
目的：脱嘌呤/脱嘧啶核酸内切酶（Apurinic/apyrimidinic endonuclease，APE 1）是一种双功能AP核酸内切酶/氧化还原因子，在DNA修复和氧化还原信号转导中起重要作用，可能与化疗耐药有关。在本研究中，我们首先研究了APE 1在非小细胞肺癌（NSCLC）患者中的表达及其与顺铂耐药和预后的关系。然后，我们研究了携带人APE 1 siRNA的嵌合腺病毒载体Ad 5/F35（Ad 5/F35-APE 1 siRNA）对A549人肺腺癌细胞顺铂敏感性的影响。在这些患者中，72例患者已接受至少3个周期的顺铂为基础的化疗。分别用免疫组化和Western blot检测肿瘤标本和培养的A549细胞系中APE 1蛋白的表达。结果：83.3%（20/24）的顺铂耐药肿瘤表达APE 1，而8.3%（4/48）的顺铂敏感肿瘤表达APE 1（P < 0.01）。单因素分析显示APE 1低表达的NSCLC患者的总生存期和无瘤生存期明显优于APE 1高表达的NSCLC患者（p < 0.01）。顺铂诱导A549细胞APE 1蛋白表达呈剂量依赖性增加，Ad 5/F35-APE 1 siRNA能有效抑制APE 1的表达。Ad 5/F35-APE 1 siRNA显著增强A549细胞对顺铂的敏感性，并增加细胞凋亡。结论：APE 1是NCSLC患者联合顺铂化疗的新靶点。(C)2009爱思唯尔爱尔兰有限公司保留所有权利。
Purpose: Apurinic/apyrimidinic endonuclease (APE1), a bifunctional AP endonuclease/redox factor, is important in DNA repair and redox signaling, may be associated with chemoresistance. In this study, we first investigated APE1 expression and its correlation with cisplatin resistance and prognosis in nonsmall cell lung cancer (NSCLC) patients. Then, we investigated the effect of chimeric adenoviral vector Ad5/F35 carrying human APE1 siRNA (Ad5/F35-APE1 siRNA) on the sensitivity of cisplatin in A549 human lung adenocarcinoma cells.Methods: Tumor specimens from 103 patients with operable NSCLC were obtained from 1999 to 2001. Among these patients, 72 patients have been treated with at least three cycles of cisplatin-based chemotherapy. APE1 protein expression was examined by immunohistochemistry and Western blot on the tumor samples and a cultured A549 cell line, respectively. Cell survival and apoptosis were determined by MTT and TUNEL, respectively.Results: 83.3% (20/24) cisplatin-resistant tumors showed high APE1 expression levels, while 8.3% (4/48) cisplatin-sensitive tumors showed high APE1 expression levels (p < 0.01). Univariate analysis indicated that overall survival and disease-free survival were significantly better in NSCLC patients with low vs those with high APE1 expression levels (p < 0.01). Treatment with cisplatin resulted in a dose-dependent increase in APE1 protein expression in A549 cells, and Ad5/F35-APE1 siRNA effectively inhibited APE1 expression. Ad5/F35-APE1 siRNA significantly enhanced sensitivity of A549 cells to cisplatin, associated with increased cell apoptosis.Conclusions: Our results indicate that APE1 is a new promising target for the combination of cisplatin-based chemotherapy in NCSLC patients. (C) 2009 Elsevier Ireland Ltd. All rights reserved.