Resveratrol inhibits age-dependent spontaneous tumorigenesis by SIRT1-mediated post-translational modulations in the annual fish Nothobranchius guentheri.
Resveratrol inhibits age-dependent spontaneous tumorigenesis by SIRT1-mediated post-translational modulations in the annual fish Nothobranchius guentheri.
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白藜芦醇通过 SIRT1 介导的翻译后调节抑制一年生鱼类 Nothobranchius guentheri 的年龄依赖性自发肿瘤发生
DOI：
10.18632/oncotarget.19268
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发表时间：
2017-08-15
期刊：
影响因子：
--
通讯作者：
Li G
中科院分区：
文献类型：
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作者：
Liu T;Ma L;Zheng Z;Li F;Liu S;Xie Y;Li G
白藜芦醇是SIRT1激活剂，主要抑制转基因动物模型、裸鼠原位癌或不同癌细胞系的致癌作用，但其在脊椎动物模型自发肿瘤过程中的作用仍未得到验证。自发性肝肿瘤是一种与年龄相关的疾病，白藜芦醇对一年生鱼类Nothobranchius guentheri的自发性肝肿瘤有抑制作用，表明该鱼可以作为研究自发性肿瘤发生的良好模型。总共给175条鱼喂了白藜芦醇，另有175条鱼作为对照。处理的鱼从性成熟(4个月龄)开始喂白藜芦醇(25μg/鱼/天)，直到6个月、9个月和12个月龄处死。采用免疫印迹、免疫组织化学和免疫共沉淀等方法研究了白藜芦醇抑制鱼类年龄依赖性自发肿瘤发生的可能机制。结果表明，白藜芦醇可提高SIRT1的蛋白水平，减轻与年龄相关的肝脏肿瘤的发生。在SIRT1上调的作用下，白藜芦醇通过去乙酰化K-RAS和失活K-RAS/PI3K/AKT途径抑制细胞增殖，通过Foxos去乙酰化和去磷酸化、DLC1上调和SIRT1与DLC1的相互作用以及DLC1去磷酸化促进自发肿瘤细胞的凋亡。我们建立了一个新的短寿命FISH模型，用于了解药物对年龄依赖性自发肿瘤发生的分子机制。
Resveratrol, SIRT1 activator, inhibits carcinogenesis predominantly performed in transgenic animal models, orthotopic cancers of nude mice or different cancer cell lines, but its effects during process of spontaneous tumors using vertebrate models remain untested. Spontaneous liver neoplasm is an age-related disease and is inhibited by resveratrol in the annual fish Nothobranchius guentheri, which indicates that the fish can act as an excellent model to study spontaneous tumorigenesis. Totally, 175 fish were fed with resveratrol and another 175 fish for controls. Treated fish were fed with resveratrol (25 μg/fish/day) from sexual maturity (4-month-old) until they were sacrificed at 6-, 9- and 12-month-old. Immunoblot, immunohistochemistry and co-immunoprecipitation were employed to investigate the underlying mechanisms that resveratrol inhibited age-dependent spontaneous tumorigenesis in the fish. Results showed that resveratrol increased protein level of SIRT1 and alleviated age-associated tumorigenesis in liver. With SIRT1 up-regulation, resveratrol reduced proliferation by deacetylating K-Ras and inactivating K-Ras/PI3K/AKT pathway; and promoted apoptosis through deacetylation and dephosphorylation of FoxOs, up-regulation of DLC1 and interaction between SIRT1 and DLC1, and dephosphorylation of DLC1 in spontaneous neoplasms. We established a novel short-lived fish model for understanding the molecular mechanisms of drugs on age-dependent spontaneous tumorigenesis.