title: Spermidine Prolongs Lifespan and Prevents Liver Fibrosis and Hepatocellular Carcinoma by Activating MAP1S-Mediated Autophagy.
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.
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, Texas.
authors.forename: Fei
authors.initials: F
authors.lastname: Yue
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, Texas.
authors.forename: Wenjiao
authors.initials: W
authors.lastname: Li
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, Texas.
authors.forename: Jing
authors.initials: J
authors.lastname: Zou
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, Texas.|The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China.
authors.forename: Xianhan
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, Texas.|The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China.
authors.forename: Guibin
authors.initials: G
authors.lastname: Xu
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, Texas.
authors.forename: Hai
authors.initials: H
authors.lastname: Huang
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, Texas. lliu@ibt.tamhsc.edu.|The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China.|Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University, College Station, Texas.
authors.forename: Leyuan
authors.initials: L
authors.lastname: Liu
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D013095:Spermidine / Q000627:therapeutic use*
chemical_list: D008869:Microtubule-Associated Proteins; D013095:Spermidine