Caveolin-1 mediated radioresistance of 3D grown pancreatic cancer cells
Caveolin-1 mediated radioresistance of 3D grown pancreatic cancer cells
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DOI：
10.1016/j.radonc.2009.07.004
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发表时间：
2009-09-01
影响因子：
5.7
通讯作者：
Cordes, Nils
中科院分区：
文献类型：
--
作者：
Hehlgans, Stephanie;Eke, Iris;Cordes, Nils
背景和目的：胰腺导管腺癌（PDAC）对化疗和放疗的抵抗是一个主要障碍。膜整合蛋白Caveolin-1（Cav-1）已被认为是人胰腺癌细胞中的有效靶点。在三维（3D）细胞培养模型中检查人胰腺肿瘤细胞的克隆形成存活、凋亡，在不照射和与照射组合的情况下，在siRNA介导的Cav-1敲低下的放射性DNA双链断裂和蛋白质表达及磷酸化（X射线，0-6戈伊）。免疫组化方法检测PDAC患者活检组织中Cav-1的表达。结果：PDAC中肿瘤细胞Cav-1的表达明显高于肿瘤间质。Cav-1敲低显著降低PI整合素表达和Akt磷酸化，诱导Caspase 3和Caspase 8依赖性凋亡，并增强3D细胞培养物的放射敏感性。虽然细胞周期和Cav-1启动子活性保持稳定，Cav-1敲低诱导的放射增敏与残留的DNA双链breaks.Conclusions的数目升高：我们的数据强烈支持的概念，Cav-1作为一个有效的目标，在胰腺癌细胞由于放射增敏和Cav-1过表达的肿瘤细胞PDAC。3D细胞培养是测试新型靶向策略以优化PDAC的常规放疗和化疗方案的强大而有用的工具。(C)2009爱思唯尔爱尔兰有限公司保留所有权利。放射治疗和肿瘤学92（2009）362-370
Background and purpose: Resistance of pancreatic ductal adenocarcinoma (PDAC) to chemo- and radiotherapy is a major obstacle. The integral membrane protein Caveolin-1 (Cav-1) has been suggested as a potent target in human pancreatic carcinoma cells.Materials and methods: Human pancreatic tumor cells were examined in a three-dimensional (3D) cell culture model with regard to clonogenic survival, apoptosis, radiogenic DNA-double strand breaks and protein expression and phosphorylation under siRNA-mediated knockdown of Cav-1 without and in combination with irradiation (X-rays, 0-6 Gy). Immunohistochemistry was used to assess Cav-1 expression in biopsies from patients with PDAC.Results: Tumor cells in PDAC showed significantly higher Cav-1 expression relative to tumor stroma. Cav-1 knockdown significantly reduced PI integrin expression and Akt phosphorylation, induced Caspase 3- and Caspase 8-dependent apoptosis and enhanced the radiosensitivity of 3D cell cultures. While cell cycling and Cav-1 promoter activity remained stable, Cav-1 knockdown-induced radiosensitization correlated with elevated numbers of residual DNA-double strand breaks.Conclusions: Our data strongly support the concept of Cav-1 as a potent target in pancreatic carcinoma cells due to radiosensitization and Cav-1 overexpression in tumor cells of PDAC. 3D cell cultures are powerful and useful tools for the testing of novel targeting strategies to optimize conventional radio- and chemotherapy regimes for PDAC. (C) 2009 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 92 (2009) 362-370