Celecoxib induced tumor cell radiosensitization by inhibiting radiation induced nuclear EGFR transport and DNA-repair: A COX-2 independent mechanism
Celecoxib induced tumor cell radiosensitization by inhibiting radiation induced nuclear EGFR transport and DNA-repair: A COX-2 independent mechanism
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DOI：
10.1016/j.ijrobp.2007.08.065
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发表时间：
2008-01-01
影响因子：
7
通讯作者：
Rodemann, H. Peter
中科院分区：
文献类型：
--
作者：
Dittmann, Klaus H.;Mayer, Claus;Rodemann, H. Peter
目的：阐明选择性环氧合酶（COX）-2抑制剂塞来昔布介导人肿瘤细胞放射增敏的分子机制。 方法和材料：采用支气管癌细胞A549、转化成纤维细胞HH4dd、FaDu头颈肿瘤细胞、结肠癌细胞HCT116和正常成纤维细胞HSF7进行实验。通过克隆细胞存活、Western 分析以及通过 γ H(2)AX 焦点测定对残留 DNA 损伤进行定量来评估塞来昔布治疗的效果。结果：塞来昔布治疗导致 A549、HCT116 和 HSF7 细胞显着的放射增敏，而 FaDu 和 HH4dd 细胞则没有放射增敏。观察到的放射增敏既不能与基础 COX-2 表达模式相关，也不能与基础前列腺素 E2 产生相关，而是取决于塞来昔布抑制基础和辐射诱导的表皮生长因子受体 (EGFR) 核转运的能力。在放射增敏的 A549、HSF7 和 COX-2 缺陷的 HCT116 细胞中，核 EGFR 转运受到强烈抑制，但在 FaDu 和 HH4dd 细胞中则不受抑制，这些细胞抵抗塞来昔布诱导的放射增敏。塞来昔布可抑制 A549、HSF7 和 HCT116 细胞中辐射诱导的 DNA-PK 激活，但不抑制 FaDu 和 HH4dd 细胞中的 DNA-PK 激活。因此，塞来昔布在照射后增加了残留的 γ H2AX 病灶，证明 DNA 修复的抑制仅发生在有反应的 A549、HCT116 和 HSF7 细胞中。结论：塞来昔布通过抑制 EGFR 介导的放射抗性机制（一种独立于 COX-2 活性的信号传导）来增强放射敏感性。这一新的观察结果可能具有治疗意义，即即使对于肿瘤放射抗性不依赖于 COX-2 的患者，COX-2 抑制剂也可以提高放射治疗效果。 (C) 2008 爱思唯尔公司。
Purpose: The purpose of the study was to elucidate the molecular mechanisms mediating radiosensitization of human tumor cells by the selective cyclooxygenase (COX)-2 inhibitor celecoxib.Methods and Materials: Experiments were performed using bronchial carcinoma cells A549, transformed fibroblasts HH4dd, the FaDu head-and-neck tumor cells, the colon carcinoma cells HCT116, and normal fibroblasts HSF7. Effects of celecoxib treatment were assessed by clonogenic cell survival, Western analysis, and quantification of residual DNA damage by gamma H(2)AX foci assay.Results: Celecoxib treatment resulted in a pronounced radiosensitization of A549, HCT116, and HSF7 cells, whereas FaDu and HH4dd cells were not radiosensitized. The observed radiosensitization could neither be correlated with basal COX-2 expression pattern nor with basal production of prostaglandin E2, but was depended on the ability of celecoxib to inhibit basal and radiation-induced nuclear transport of epidermal growth factor receptor (EGFR). The nuclear EGFR transport was strongly inhibited in A549-, HSF7-, and COX-2-deficient HCT116 cells, which were radiosensitized, but not in FaDu and HH4dd cells, which resisted celecoxib-induced radiosensitization. Celecoxib inhibited radiation-induced DNA-PK activation in A549, HSF7, and HCT116 cells, but not in FaDu and HH4dd cells. Consequentially, celecoxib increased residual gamma H2AX foci after irradiation, demonstrating that inhibition of DNA repair has occurred in responsive A549, HCT116, and HSF7 cells only.Conclusions: Celecoxib enhanced radiosensitivity by inhibition of EGFR-mediated mechanisms of radioresistance, a signaling that was independent of COX-2 activity. This novel observation may have therapeutic implications such that COX-2 inhibitors may improve therapeutic efficacy of radiation even in patients whose tumor radioresistance is not dependent on COX-2. (C) 2008 Elsevier Inc.