P2X7 receptor as predictor gene for glioma radiosensitivity and median survival
P2X7 receptor as predictor gene for glioma radiosensitivity and median survival
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DOI：
10.1016/j.biocel.2015.09.001
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发表时间：
2015-11-01
影响因子：
4
通讯作者：
Morrone, Fernanda B.
中科院分区：
文献类型：
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作者：
Gehring, Marina P.;Kipper, Franciele;Morrone, Fernanda B.
多形性胶质母细胞瘤（GBM）被认为是最致命的颅内肿瘤，中位生存时间约为14个月。虽然有些胶质瘤细胞存在放射抵抗性，但放射治疗一直是恶性胶质瘤患者的主要治疗手段。P2 X7受体（P2 X7 R）的激活负责ATP诱导的多种细胞类型的死亡。在本研究中，我们分析了ATP-P2 X7 R通路在放射治疗反应中的重要性P2 X7 R沉默的细胞系，在体内和人类肿瘤样品。本研究中使用的两种神经胶质瘤细胞系都存在功能性P2 X7 R，并且P2 X7 R沉默通过溴化乙锭摄取降低P2 X7 R孔活性。γ辐射（2戈伊）处理以P2 X7 R依赖的方式减少细胞数量，因为P2 X7 R拮抗剂和P2 X7 R沉默在24 h后阻断了辐射引起的细胞毒性。P2 X7 R的激活是时间依赖性的，因为在照射24小时后EtBr摄取显著增加。放射治疗加ATP孵育显着增加膜联蛋白V的掺入，与单独的放射治疗相比，表明ATP与放射治疗协同作用。值得注意的是，携带GL 261 P2 X7 R沉默的小鼠对放射治疗（8戈伊）没有反应，而携带组成性表达P2 X7 R的GL 261 WT的小鼠在放射治疗后呈现出肿瘤体积的显著减小，这表明在体内功能性P2 X7 R表达对于神经胶质瘤中的有效放射治疗反应是必需的。我们还表明，高P2 X7 R表达是一个很好的预后因素胶质瘤放射敏感性和生存概率在人类。我们的数据揭示了胶质瘤细胞中P2 X7 R表达与成功的放射治疗反应的相关性，并揭示了这种受体作为癌症患者对放射治疗敏感性和中位生存期的有用预测因子的新观点。(C)2015爱思唯尔有限公司版权所有。
Glioblastoma multiforme (GBM) is considered the most lethal intracranial tumor and the median survival time is approximately 14 months. Although some glioma cells present radioresistance, radiotherapy has been the mainstay of therapy for patients with malignant glioma. The activation of P2X7 receptor (P2X7R) is responsible for ATP-induced death in various cell types. In this study, we analyzed the importance of ATP-P2X7R pathway in the radiotherapy response P2X7R silenced cell lines, in vivo and human tumor samples. Both glioma cell lines used in this study present a functional P2X7R and the P2X7R silencing reduced P2X7R pore activity by ethidium bromide uptake. Gamma radiation (2 Gy) treatment reduced cell number in a P2X7R-dependent way, since both P2X7R antagonist and P2X7R silencing blocked the cell cytotoxicity caused by irradiation after 24h. The activation of P2X7R is time-dependent, as EtBr uptake significantly increased after 24 h of irradiation. The radiotherapy plus ATP incubation significantly increased annexin V incorporation, compared with radiotherapy alone, suggesting that ATP acts synergistically with radiotherapy. Of note, GL261 P2X7R silenced-bearing mice failed in respond to radiotherapy (8 Gy) and GL261 WT-bearing mice, that constitutively express P2X7R, presented a significant reduction in tumor volume after radiotherapy, showing in vivo that functional P2X7R expression is essential for an efficient radiotherapy response in gliomas. We also showed that a high P2X7R expression is a good prognostic factor for glioma radiosensitivity and survival probability in humans. Our data revealed the relevance of P2X7R expression in glioma cells to a successful radiotherapy response, and shed new light on this receptor as a useful predictor of the sensitivity of cancer patients to radiotherapy and median survival. (C) 2015 Elsevier Ltd. All rights reserved.