Hussain Rumana N, Coupland Sarah E, Khzouz Jakub, Kalirai Helen, Parsons Jason L
Liverpool Ocular Oncology Research Group, Department of Molecular and Clinical Cancer Medicine, William Henry Duncan Building, University of Liverpool, Liverpool L7 8TX, UK.
St Paul's Eye Clinic, Liverpool University Hospitals Foundation Trust, Prescot Street, Liverpool L7 8XP, UK.
Cancers (Basel). 2020 May 28;12(6):1388. doi: 10.3390/cancers12061388.
Treatment of uveal melanoma (UM) is generally successful, with local primary tumour control being at 90%-95%. Localized radiotherapy in the form of plaque brachytherapy or proton beam radiotherapy is the most common treatment modality in the UK. However, the basic mechanisms of radiation response, DNA repair and tissue reactions in UM have not been well documented previously. We have investigated the comparative radiosensitivity of four UM cell lines in response to exogenous radiation sources (both X-rays and protons), and correlated this with DNA repair protein expression and repair efficiency. We observed a broad range of radiosensitivity of different UM cell lines to X-rays and protons, with increased radioresistance correlating with elevated protein expression of ataxia telangiectasia mutated (ATM), a protein kinase involved in the signaling and repair of DNA double strand breaks. The use of an ATM inhibitor in UM cell lines enhanced radiosensitivity following both X-ray and proton irradiation, particularly in cells that contained high levels of ATM protein which are otherwise comparatively radioresistant. In proton-irradiated compared with non-irradiated primary enucleated UM patient samples, there was no significant difference in ATM protein expression. Our study therefore suggests that ATM is a potential target for increasing the radiosensitivity of more resistant UM subgroups.
葡萄膜黑色素瘤（UM）的治疗通常是成功的，局部原发性肿瘤控制率达90%-95%。在英国，以斑块近距离放射疗法或质子束放射疗法形式的局部放射治疗是最常见的治疗方式。然而，此前UM中辐射反应、DNA修复和组织反应的基本机制尚未得到充分记录。我们研究了四种UM细胞系对外源辐射源（X射线和质子）的相对放射敏感性，并将其与DNA修复蛋白表达和修复效率相关联。我们观察到不同UM细胞系对X射线和质子具有广泛的放射敏感性，放射抗性增加与共济失调毛细血管扩张症突变（ATM）蛋白表达升高相关，ATM是一种参与DNA双链断裂信号传导和修复的蛋白激酶。在UM细胞系中使用ATM抑制剂可增强X射线和质子照射后的放射敏感性，特别是在含有高水平ATM蛋白因而具有相对放射抗性的细胞中。与未照射的原发性眼球摘除UM患者样本相比，质子照射样本中ATM蛋白表达没有显著差异。因此，我们的研究表明，ATM是提高更具抗性的UM亚组放射敏感性的潜在靶点。
