Spermidine Prolongs Lifespan and Prevents Liver Fibrosis and Hepatocellular Carcinoma by Activating MAP1S-Mediated Autophagy

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
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]
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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