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Cancer Res. 2017 Jun 1;77(11):2938-2951. doi: 10.1158/0008-5472.CAN-16-3462. Epub 2017 Apr 6.

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

Yue F1, Li W1, Zou J1, Jiang X1,2, Xu G1,2, Huang H1, Liu L3,2,4.

Author information

1
Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, Texas.
2
The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China.
3
Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, Texas. lliu@ibt.tamhsc.edu.
4
Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University, College Station, Texas.

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.

PMID:
28386016
PMCID:
PMC5489339
DOI:
10.1158/0008-5472.CAN-16-3462
[Indexed for MEDLINE]
Free PMC Article

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