Fibroblasts from Retinoblastoma Patients Show Radiosensitivity Linked to Abnormal Localization of the ATM Protein
Fibroblasts from Retinoblastoma Patients Show Radiosensitivity Linked to Abnormal Localization of the ATM Protein
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DOI：
10.1080/02713683.2020.1808998
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发表时间：
2020-08-31
影响因子：
2
通讯作者：
Foray, Nicolas
中科院分区：
文献类型：
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作者：
Lakhdar, Ismahane Moulay;Ferlazzo, Melanie L.;Foray, Nicolas
研究目的：视网膜母细胞瘤（Rb）是一种罕见的儿科癌症，从视网膜细胞发展而来。Rb的双侧和某些单侧形式与（视网膜母细胞瘤1）RB 1基因的杂合子生殖系突变相关。RB 1突变也与继发性恶性肿瘤（如头颈部肿瘤）的显著风险相关。因此，迄今为止，即使Rb患者较少接受放射治疗来治疗其原发性眼部肿瘤，其健康组织也可能在针对其继发性恶性肿瘤的治疗期间暴露于显著剂量的电离辐射，具有不良组织反应（放射敏感性）和/或辐射诱导的癌症（放射敏感性）的显著风险。然而，Rb蛋白在辐射反应中的生物学作用仍然被误解。由于共济失调毛细血管扩张突变（ATM）蛋白是辐射反应的关键蛋白，并且由于未转化的皮肤成纤维细胞是量化细胞辐射敏感性的当前模型，我们在此首次研究了来自Rb患者的辐射皮肤成纤维细胞中辐射诱导的DNA双链断裂（DSB）的ATM依赖性信号传导和修复途径的功能。DSB修复和信号传导的主要生物标志物，即克隆形成细胞存活、微核、H2 A组蛋白X变体磷酸化形式的核灶在来自三名Rb患者的未转化皮肤成纤维细胞中评估了γ H2 AX、ATM蛋白的磷酸化形式（pATM）和减数分裂重组11核酸酶（MRE 11）。Rb患者的皮肤成纤维细胞表现出显著的细胞放射敏感性、不完全的DSB识别、ATM核穿梭延迟和加剧的MRE 11核酸酶活性。他汀类药物和双磷酸盐治疗导致这些implementations.Conclusions显着的互补：我们的研究结果强烈表明，ATM激酶参与Rb病例中观察到的放射敏感性/放射敏感性表型。
Purpose/Aim of the study: Retinoblastoma (Rb) is a rare form of pediatric cancer that develops from retina cells. Bilateral and some unilateral forms of Rb are associated with heterozygous germline mutations of the (retinoblastoma 1) RB1 gene. RB1 mutations are also associated with a significant risk of secondary malignancy like head and neck tumors. Hence, to date, even if Rb patients are less subjected to radiotherapy to treat their primary ocular tumors, their healthy tissues may be exposed to significant doses of ionizing radiation during the treatment against their secondary malignancies with a significant risk of adverse tissue reactions (radiosensitivity) and/or radiation-induced cancer (radiosusceptibility). However, the biological role of the Rb protein in response to radiation remains misunderstood. Since the ataxia telangiectasia mutated (ATM) protein is a key protein of radiation response and since untransformed skin fibroblasts are a current model to quantify cellular radiosensitivity, we investigated here for the first time the functionality of the ATM-dependent signaling and repair pathway of the radiation-induced DNA double-strand breaks (DSB) in irradiated skin fibroblasts derived from Rb patientsMaterials and methods: The major biomarkers of the DSB repair and signaling, namely clonogenic cell survival, micronuclei, nuclear foci of the phosphorylated forms of the X variant of the H2A histone (gamma H2AX), the phosphorylated forms of the ATM protein (pATM) and the meiotic recombination 11 nuclease (MRE11) were assessed in untransformed skin fibroblasts derived from three Rb patients.Results: Skin fibroblasts from Rb patients showed significant cellular radiosensitivity, incomplete DSB recognition, delay in the ATM nucleo-shuttling and exacerbated MRE11 nuclease activity. Treatment with statin and bisphosphonates led to significant complementation of these impairments.Conclusions: Our findings strongly suggest the involvement of the ATM kinase in the radiosensitivity/ radiosusceptibility phenotype observed in Rb cases.