Adenoviral-mediated gene transfer of Gadd45a results in suppression by inducing apoptosis and cell cycle arrest in pancreatic cancer cell
Adenoviral-mediated gene transfer of Gadd45a results in suppression by inducing apoptosis and cell cycle arrest in pancreatic cancer cell
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DOI：
10.1002/jgm.1270
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发表时间：
2009-01-01
影响因子：
3.5
通讯作者：
Lin, Chen
中科院分区：
文献类型：
--
作者：
Li, Yunfeng;Qian, Haili;Lin, Chen
背景胰腺导管腺癌患者预后极差，需要新的治疗方法。生长阻滞和DNA损伤诱导（Gadd）基因Gadd45a是由DNA损伤剂和生长阻滞信号诱导的一组基因中的一员。方法研究Gadd45a在胰腺导管腺癌衍生细胞系中的生物活性，并评估腺病毒介导的Gadd45a （AdG45a）表达与抗癌药物（分别为依托泊苷、顺铂、5-氟尿嘧啶）联合治疗胰腺导管腺癌衍生细胞系PANC1的疗效。结果Gadd45a在胰腺导管腺癌细胞系中有多种表达，腺病毒介导的Gadd45a （Ad-G45a）在这些细胞中的表达通过caspase激活和G2/M期细胞周期阻滞导致细胞凋亡。Gadd45a显著增加了PANC1的化学敏感性，这可能与丰富的凋亡诱导和细胞周期阻滞有关。通过Ad-G45a感染和化疗药物的联合治疗，Gadd45a在p53野生型的癌细胞中表达水平高于p53敲除状态的癌细胞，表明其对癌症化疗具有更高的化疗敏感性。结论Gadd45a与化疗药物联合应用于肿瘤基因治疗是一种很有前景的候选药物。版权所有(C) 2008约翰威利父子有限公司
Background The extremely poor prognosis of patients with pancreatic ductal adenocarcinoma indicates the need for novel therapeutic approaches. The growth arrest and DNA damage-inducible (Gadd) gene Gadd45a is a member of a group of genes that are induced by DNA damaging agents and growth arrest signals.Methods We evaluated the biological activity of Gadd45a in pancreatic ductal adenocarcinoma cancer-derived cell lines and assessed the efficacy of a combined treatment with adenoviral-mediated expression of Gadd45a (AdG45a) and anticancer drug (Etoposide, cisplatin, 5-fluorouracil, respectively) for the PANC1 cell line.Results Gadd45a is variously expressed in cell lines derived from pancreatic ductal adenocarcinoma cancer and adenoviral-mediated expression of Gadd45a (Ad-G45a) in these cells results in apoptosis via caspase activation and cell-cycle arrest in the G2/M phase. Gadd45a significantly increased the chemosensitivity of PANC1, which may be due to abundant apoptosis induction and cell cycle arrest. By combinational treatment of Ad-G45a infection and chemotherapeutics, Gadd45a expression was elevated to a higher extent in cancer cells with wild-type p53 than in that with knocked-out p53 status, indicating a higher chemosensitivity to cancer chemotherapy.Conclusions Gadd45a may be a promising candidate for use in cancer gene therapy in combination with chemotherapeutic agents. Copyright (C) 2008 John Wiley & Sons, Ltd.