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.
Highlights
Hepatocellular carcinoma (HCC) is the most common form of liver cancers and has become a serious problem in the US in recent decades [1]
Here we show that spermidine increases the acetylation and stability of Microtubule-associated protein 1S (MAP1S) and activates autophagy flux by depleting cytosolic HDAC4 to reduce the association between MAP1S and HDAC4
Acetylation of MAP1S activates autophagy; and MAP1S depletion leads to an elevation in oxidative stress and intensity of sinusoidal dilatation in mouse liver tissues; and wild-type mice live a median lifespan of 28.0 months while MAP1S−/− mice live a median lifespans of 22.4 months [16,19]
Summary
Hepatocellular carcinoma (HCC) is the most common form of liver cancers and has become a serious problem in the US in recent decades [1]. Most HCC patients develop liver cirrhosis caused by liver fibrosis; and liver cirrhosis itself is the most common nonneoplastic cause of mortality among hepatobiliary and digestive diseases in the US [1,2]. Hepatitis B virus (HBV) immunization and antiviral therapy against HBV or hepatitis C virus (HCV) in established patients can reduce HCC risk, their cost-effectiveness for HCC prevention in the general population is unknown. Prescribed medications such as statins, metformin and aspirin have shown chemo-preventive effects for HCC, but each simultaneously exhibits other unintended effects [3]. Natural dietary components and phytochemicals consumed by humans over their lifetime provide a great window of opportunity to prevent or change the pathogenic course of the disease in a safer and more cost-effective way
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