Abstract
Alterations of methionine cycle in steatohepatitis, cirrhosis, and hepatocellular carcinoma induce MAT1A decrease and MAT2A increase expressions with the consequent decrease of S-adenosyl-L-methionine (SAM). This causes non-alcoholic fatty liver disease (NAFLD). SAM administration antagonizes pathological conditions, including galactosamine, acetaminophen, and ethanol intoxications, characterized by decreased intracellular SAM. Positive therapeutic effects of SAM/vitamin E or SAM/ursodeoxycholic acid in animal models with NAFLD and intrahepatic cholestasis were not confirmed in humans. In in vitro experiments, SAM and betaine potentiate PegIFN-alpha-2a/2b plus ribavirin antiviral effects. SAM plus betaine improves early viral kinetics and increases interferon-stimulated gene expression in patients with viral hepatitis non-responders to pegIFNα/ribavirin. SAM prevents hepatic cirrhosis, induced by CCl4, inhibits experimental tumors growth and is proapoptotic for hepatocellular carcinoma and MCF-7 breast cancer cells. SAM plus Decitabine arrest cancer growth and potentiate doxorubicin effects on breast, head, and neck cancers. Furthermore, SAM enhances the antitumor effect of gemcitabine against pancreatic cancer cells, inhibits growth of human prostate cancer PC-3, colorectal cancer, and osteosarcoma LM-7 and MG-63 cell lines; increases genomic stability of SW480 cells. SAM reduces colorectal cancer progression and inhibits the proliferation of preneoplastic rat liver cells in vivo. The discrepancy between positive results of SAM treatment of experimental tumors and modest effects against human disease may depend on more advanced human disease stage at moment of diagnosis.
Highlights
In 1951, Cantoni discovered the enzymatic formation of SAM, by the nucleophilic transfer of the adenosyl moiety of adenosinetriphosphate (ATP) to the sulphur atom of Lmethionine [1] (Figure 1), which has been thereafter studied extensively in liver cancer [2,3].SAM is the first product of the “methionine cycle” and is implicated in the synthesis of polyamines and in the transsulfuration pathway leading to homocysteine and reduced glutathione (GSH) biosynthesis (Figure 2)
SAM is synthesized from methionine and ATP in a reaction catalyzed by methionine adenosyltransferases (MATs) [4]
The methionine cycle plays a fundamental role in the cellular metabolism and the alteration of its functionality causes important disorders linked to modification of DNA methylation and gene expression, redox imbalance and metabolic reprogramming in liver and brain [12,13,14,15]
Summary
In 1951, Cantoni discovered the enzymatic formation of SAM, by the nucleophilic transfer of the adenosyl moiety of adenosinetriphosphate (ATP) to the sulphur atom of Lmethionine [1] (Figure 1), which has been thereafter studied extensively in liver cancer [2,3]. SAM is synthesized from methionine and ATP in a reaction catalyzed by methionine adenosyltransferases (MATs) [4] These enzymes are encoded by two genes, MAT1A and MAT2A. Decarboxylated SAM (dSAM) (Figure 2) is used for the synthesis of polyamines and 5 -methylthioadenosine (MTA) The latter, after transformation to methylthioribose by a specific nucleosidase, may be further used in the “salvage pathway” of methionine re-synthesis [7]. HCY may be transformed by a synthetase to cystathionine, a precursor of GSH, or is methylated for the resynthesis of methionine (Figure 2). This resynthesis, catalyzed by betaine homocysteine methyltransferase, may be coupled to the Bremer pathway [8,9] for the synthesis of phosphatidylcholine from phosphatidylethanolamine by phosphatidylethanolamine methyltransferase (PEMT). The methionine cycle plays a fundamental role in the cellular metabolism and the alteration of its functionality causes important disorders linked to modification of DNA methylation and gene expression, redox imbalance and metabolic reprogramming in liver and brain [12,13,14,15]
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