FoxO1 is involved in the antineoplastic effect of calorie restriction
FoxO1 is involved in the antineoplastic effect of calorie restriction
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DOI：
10.1111/j.1474-9726.2010.00563.x
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发表时间：
2010-06
期刊：
影响因子：
7.8
通讯作者：
H. Yamaza;Toshimitsu Komatsu;Saori Wakita;Carole Kijogi;Seongjoon Park;H. Hayashi;T. Chiba;Ryoichi Mori;T. Furuyama;N. Mori;I. Shimokawa
中科院分区：
文献类型：
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作者：
H. Yamaza;Toshimitsu Komatsu;Saori Wakita;Carole Kijogi;Seongjoon Park;H. Hayashi;T. Chiba;Ryoichi Mori;T. Furuyama;N. Mori;I. Shimokawa
FoxO转录因子可能参与了限热量（CR）对哺乳动物的抗衰老作用。为了验证这一假设，我们使用了FoxO 1敲除杂合子（HT）小鼠，其中FoxO 1 mRNA水平降低了野生型（WT）小鼠组织的50%或更低。WT和HT小鼠从12周龄起随意饲喂（AL）或30% CR饲料。在寿命研究中，WT和HT小鼠之间体重、摄食量、血糖和胰岛素浓度的衰老和CR相关变化相似。在6月龄时，在肝脏和海马中评价了通过腹膜内注射3-硝基丙酸（3-NPA）诱导的对氧化应激的反应。3-NPA注射后，WT-CR组织中几种选定的FoxO 1-靶基因（用于细胞周期阻滞、DNA修复、细胞凋亡和应激抗性）上调，而HT-CR组织中的作用大部分减弱。在这些基因产物中，我们重点关注肝脏中的核p21蛋白水平，并证实其仅在WT-CR小鼠中响应氧化应激而上调。在AL或CR条件下，WT和HT小鼠的寿命没有显著差异。然而，CR的抗肿瘤作用（如WT-CR小鼠死亡时肿瘤发生率降低所示）在HT-CR小鼠中大部分消失。目前的研究结果表明，FoxO 1在CR的抗氧化作用中的作用，通过诱导负责保护免受氧化和遗传毒性应激的基因。
The FoxO transcription factors may be involved in the antiaging effect of calorie restriction (CR) in mammals. To test the hypothesis, we used FoxO1 knockout heterozygotic (HT) mice, in which the FoxO1 mRNA level was reduced by 50%, or less, of that in wild‐type (WT) mouse tissues. The WT and HT mice were fed ad libitum (AL) or 30% CR diets from 12 weeks of age. Aging‐ and CR‐related changes in body weight, food intake, blood glucose, and insulin concentrations were similar between the WT and HT mice in the lifespan study. The response to oxidative stress, induced by intraperitoneal injection of 3‐nitropropionic acid (3‐NPA), was evaluated in the liver and hippocampus at 6 months of age. Several of the selected FoxO1‐target genes for cell cycle arrest, DNA repair, apoptosis, and stress resistance were up‐regulated in the WT‐CR tissues after 3‐NPA injection, while the effect was mostly diminished in the HT‐CR tissues. Of these gene products, we focused on the nuclear p21 protein level in the liver and confirmed its up‐regulation only in the WT‐CR mice in response to oxidative stress. The lifespan did not differ significantly between the WT and HT mice in AL or CR conditions. However, the antineoplastic effect of CR, as indicated by reduced incidence of tumors at death in the WT‐CR mice, was mostly abrogated in the HT‐CR mice. The present results suggest a role for FoxO1 in the antineoplastic effect of CR through the induction of genes responsible for protection against oxidative and genotoxic stress.