Spermidine Prolongs Lifespan and Prevents Liver Fibrosis and Hepatocellular Carcinoma by Activating MAP1S-Mediated Autophagy.
Spermidine Prolongs Lifespan and Prevents Liver Fibrosis and Hepatocellular Carcinoma by Activating MAP1S-Mediated Autophagy.
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DOI：
10.1158/0008-5472.can-16-3462
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发表时间：
2017-06-01
期刊：
影响因子：
11.2
通讯作者：
Liu L
中科院分区：
文献类型：
--
作者：
Yue F;Li W;Zou J;Jiang X;Xu G;Huang H;Liu L
肝纤维化和肝细胞癌 (HCC) 具有世界范围的影响，但仍然缺乏安全、低成本和有效的治疗方法。在这项研究中，我们展示了简单的聚胺亚精胺如何缓解癌细胞自噬缺陷，从而引发氧化应激诱导的细胞死亡并促进肝纤维化和肝癌。我们发现自噬标记蛋白 LC3 与微管相关蛋白 MAP1S 相互作用，从而正向调节细胞中的自噬通量。 MAP1S 的稳定性反过来又通过其与组蛋白脱乙酰酶 HDAC4 的相互作用来调节。值得注意的是，MAP1S 缺陷小鼠的中位生存期降低了 20%，并在压力下出现严重的肝纤维化和 HCC。用亚精胺处理的野生型小鼠或细胞通过消耗胞质 HDAC4 表现出 MAP1S 稳定性和自噬信号传导的相对增加。最近的证据表明，口服亚精胺可以延长小鼠的寿命，我们确定，终身服用亚精胺可以延长高达 25% 的寿命，同时还可以减少化学损伤引起的肝纤维化和肝癌病灶。遗传学研究表明，口服亚精胺的这些观察到的影响依赖于 MAP1S 介导的自噬。我们的研究结果为口服亚精胺预防肝纤维化和肝癌并有可能延长寿命提供了临床前概念证明。
Liver fibrosis and hepatocellular carcinoma (HCC) have worldwide impact but continue to lack safe, low cost and effective treatments. In this study, we show how the simple polyamine spermidine can relieve cancer cell defects in autophagy which trigger oxidative stress-induced cell death and promote liver fibrosis and HCC. We found that the autophagic marker protein LC3 interacted with the microtubule-associated protein MAP1S which positively regulated autophagy flux in cells. MAP1S stability was regulated in turn by its interaction with the histone deacetylase HDAC4. Notably, MAP1S-deficient mice exhibited a 20% reduction in median survival and developed severe liver fibrosis and HCC under stress. Wild-type mice or cells treated with spermidine exhibited a relative increase in MAP1S stability and autophagy signaling via depletion of cytosolic HDAC4. Extending recent evidence that orally administered spermidine can extend lifespan in mice, we determined that life extension of up to 25% can be produced by lifelong administration which also reduced liver fibrosis and HCC foci as induced by chemical insults. Genetic investigations established that these observed impacts of oral spermidine administration relied upon MAP1S-mediated autophagy. Our findings offer a preclinical proof of concept for the administration of oral spermidine to prevent liver fibrosis and HCC and potentially extend lifespan.