Selenoprotein P inhibits radiation-induced late reactive oxygen species accumulation and normal cell injury.
Selenoprotein P inhibits radiation-induced late reactive oxygen species accumulation and normal cell injury.
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DOI：
10.1016/j.ijrobp.2013.06.2063
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发表时间：
2013-11-01
影响因子：
7
通讯作者：
Goswami, Prabhat C.
中科院分区：
文献类型：
--
作者：
Eckers, Jaimee C.;Kalen, Amanda L.;Xiao, Wusheng;Sarsour, Ehab H.;Goswami, Prabhat C.
放射是癌症治疗的常见模式，其结果通常由于正常组织毒性而受到限制。我们以前已经表明，辐射诱导的晚期活性氧（ROS）的积累先于细胞死亡，这表明代谢性氧化应激可以调节细胞的辐射反应。本研究的目的是调查，如果硒蛋白P（SEPP 1），硒的主要供应商组织和抗氧化剂，调节辐射正常人成纤维细胞（NHF）的后期ROS积累和毒性。流式细胞术分析细胞活力，细胞周期时相分布和DHE氧化以及克隆形成试验用于测量氧化应激和毒性。使用人类抗氧化机制阵列（Applied Biosystems）和Q-RT-PCR测定来测量在辐照的NHF中晚期ROS积累期间的基因表达。亚硒酸钠添加和sepp 1过表达被用来确定SEPP 1调节后期ROS积累和辐照NHF毒性的因果关系。辐照的NHF表现出晚期ROS积累（相对于对照增加4.5倍; p<0.05），其发生在细胞周期检查点途径激活之后并且在细胞死亡之前。CuZn-和Mn-超氧化物歧化酶、过氧化氢酶、过氧化物氧还蛋白3和硫氧还蛋白还原酶1的mRNA水平增加约2至3倍，而包含E1和SEPP 1的冷休克结构域的mRNA水平增加超过6倍（p<0.05）。在放射治疗前添加亚硒酸钠抑制毒性（45%; p<0.05）。SEPP 1过表达抑制辐射诱导的晚期ROS积累（35%; p<0.05）并保护NHF免受辐射诱导的毒性（58%; p<0.05）。SEPP 1减轻辐射诱导的晚期ROS积累和正常细胞损伤。
Radiation is a common mode of cancer therapy whose outcome is often limited due to normal tissue toxicity. We have shown previously that radiation-induced late reactive oxygen species (ROS) accumulation precedes cell death, suggesting that metabolic oxidative stress could regulate cellular radiation response. The purpose of this study is to investigate if selenoprotein P (SEPP1), a major supplier of selenium to tissues and an antioxidant, regulates late ROS accumulation and toxicity in irradiated normal human fibroblasts (NHFs). Flow cytometry analysis of cell viability, cell cycle phase distribution and DHE-oxidation as well as clonogenic assays were used to measure oxidative stress and toxicity. Human Antioxidant Mechanisms Array (Applied Biosystems) and Q-RT-PCR assays were used to measure gene expression during late ROS accumulation in irradiated NHFs. Sodium selenite addition and sepp1 overexpression were used to determine the causality of SEPP1 regulating late ROS accumulation and toxicity in irradiated NHFs. Irradiated NHFs exhibit late ROS accumulation (4.5-fold increase from control; p<0.05) that occurs after the activation of the cell cycle checkpoint pathways and precedes cell death. mRNA levels of CuZn- and Mn-superoxide dismutase, catalase, peroxiredoxin 3, and thioredoxin reductase 1 increased approximately 2-to-3-fold, while mRNA levels of cold shock domain containing E1 and SEPP1 increased more than 6-fold (p<0.05). Addition of sodium selenite prior to the radiation treatment suppressed toxicity (45%; p<0.05). SEPP1 overexpression suppressed radiation-induced late ROS accumulation (35%; p<0.05) and protected NHFs from radiation-induced toxicity (58%; p<0.05). SEPP1 mitigates radiation-induced late ROS accumulation and normal cell injury.
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