亚精胺
自噬
癌症研究
肝癌
纤维化
HDAC4型
肝细胞癌
ATG5型
癌症
多胺
药理学
生物
医学
内科学
细胞凋亡
组蛋白脱乙酰基酶
组蛋白
生物化学
基因
酶
作者
Yue Fei,Wenjiao Li,Jing Zou,Xianhan Jiang,Guibin Xu,Hai Huang,Leyuan Liu
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2017-04-07
卷期号:77 (11): 2938-2951
被引量:135
标识
DOI:10.1158/0008-5472.can-16-3462
摘要
Abstract 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. Cancer Res; 77(11); 2938–51. ©2017 AACR.
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