SirT1 regulates radiosensitivity of hepatoma cells differently under normoxic and hypoxic conditions
SirT1 regulates radiosensitivity of hepatoma cells differently under normoxic and hypoxic conditions
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SirT1在常氧和低氧条件下不同地调节肝癌细胞的放射敏感性
DOI：
10.1111/j.1349-7006.2012.02285.x
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发表时间：
2012-07-01
期刊：
影响因子：
5.7
通讯作者：
Shao, Chunlin
中科院分区：
文献类型：
--
作者：
Xie, Yuexia;Zhang, Jianghong;Shao, Chunlin
肿瘤内低氧细胞对放疗的抵抗力更强，这是由于DNA损伤自由基的寿命缩短和照射后分子修复的增加。SIRT1是哺乳动物sirtuin家族中的一员，它通过去乙酰化各种转录因子来触发细胞防御和生存，以应对压力和DNA损伤。在这项研究中，我们提供了新的证据表明，SirT1在肝癌HepG2细胞中的过表达使细胞在低氧条件下比在常氧条件下对辐射的抵抗力更强。当SirT1在HepG2和SK-Hep-1细胞中均被敲除时，放射敏感性增加，尤其是在低氧条件下。但是，通过感染c-Myc siRNA，SirT1缺陷细胞的这种增强的辐射敏感性被广泛地降低。此外，SirT1基因敲除细胞中c-Myc蛋白的表达及其乙酰化水平均增加，且在低氧条件下这种增加比常氧条件下更为显著。此外，c-Myc干扰显著抑制辐射后磷酸化P53蛋白的表达，特别是在低氧条件下。目前的研究结果表明，SirT1在低氧细胞中表现出比正常细胞更高的辐射抗性，这是由于c-Myc蛋白及其乙酰化水平的降低，并且可能参与了c-Myc依赖的辐射诱导的磷酸化P53。SIRT1可以作为一个新的放射损伤靶点，从而成为提高肝癌实体放射治疗效率的潜在策略。(《癌症科学》2012年版，第103期：12381244页)
Intratumoral hypoxic cells are more resistant to radiotherapy due to a reduction in lifespan of DNA-damaging free radicals and augmentation of post-irradiation molecular restoration. SirT1, a member of the mammalian sirtuin family, deacetylates various transcription factors to trigger cell defense and survival in response to stresses and DNA damage. In this study, we provide new evidence indicating that overexpression of SirT1 in hepatoma HepG2 cells allowed the cells to become much more resistant to irradiation under hypoxia than under normoxia. When SirT1 was knocked down in both HepG2 and SK-Hep-1 cells, the radiosensitivity was increased, especially under hypoxia. But this enhanced radiosensitivity in SirT1-deficient cells was extensively decreased by infecting cells with c-Myc siRNA. Furthermore, the expression of c-Myc protein and its acetylation were increased in the SirT1 knockdown cells and these increments under hypoxic conditions were much more notable than under normoxia. In addition, c-Myc interference significantly suppressed phosphorylated p53 protein expression after irradiation, especially under hypoxic conditions. The current findings indicate that SirT1 confers a higher radioresistance in hypoxic cells than in normoxic cells due to the decreased levels of c-Myc protein and its acetylation, and that a c-Myc-dependent radiation-induced phosphorylated p53 may be involved. SirT1 could serve as a novel target of radiation damage and thus as a potential strategy to advance the efficiency of radiotherapy in hepatoma entities. (Cancer Sci 2012; 103: 12381244)