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Review
. 2022 Jan 25;11(3):409.
doi: 10.3390/cells11030409.

S-Adenosylmethionine: From the Discovery of Its Inhibition of Tumorigenesis to Its Use as a Therapeutic Agent

Rosa M Pascale  1 , Maria M Simile  1 , Diego F Calvisi  1 , Claudio F Feo  2 , Francesco Feo  1
Affiliations
Review

S-Adenosylmethionine: From the Discovery of Its Inhibition of Tumorigenesis to Its Use as a Therapeutic Agent

Rosa M Pascale et al. Cells. .

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.

Keywords: S-adenosyl-L-methionine; alcoholic liver disease; intra-hepatic cholestasis; methionine cycle; non-alcoholic fatty liver; viral hepatitis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Synthesis of S-adenosylmethionine.
Figure 2
Figure 2
Metabolic cycles involved in methionine metabolism. Substrates: BET, betaine; CHOL, choline; DMG, dimethylglycine; dSAM, decarboxylated S-adenosylmethionine; GN, glycine; GSH, reduced glutathione; HCY, homocysteine; MeTHF, 5,10-methylenetetrahydrofolate; MTA, 5-methylthioadenosine; MTHF, 5-methyltetrahydrofolate; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine; SN, sarcosine; THF, tetrahydrofolate. Enzymes: BHMT, betaine homocysteine methyltransferase; DMGDH, dimethylglycine dehydrogenase; GNMT, glycine n-methyltransferase; MATI/III, methyladenosyltransferase I/III; MATII, methyladenosyltransferase II; MeTHFR 5,10-methyltetrahydrofolate reductase; MT, various methyltransferases; PEMT, phosphatidylethanolamine N–methyltransferase; SAHH, S-adenosylhomocysteine hydroxylase; SD, SAM decarboxylase.
Figure 3
Figure 3
SAM and SAH long-range interactions. BET: betaine; BHMT: betaine homocysteine methyltransferase; dMGN: dimethylglycine; HCY: homocysteine; MATI/III: methionine adenosyltransferase I/III; MATII: methionine adenosyltransferase II; GN: glycine; GNMT: glycine methyltransferase; GSH, reduced glutathione; Me-THF: 5,10-methylenetetrahydrofolate; MHMT: methyltetrahydrofolate homocysteine methyltransferase; PC: phosphatidylcholine; PE: phosphatidylethanolamine; SAH: S-adenosylhomocysteine; SAM: S-adenosylmethionine; SN: sarcosine. Arrows indicate activation; blunt arrows indicate inhibition.
Figure 4
Figure 4
Effects of SAM on signal transduction pathways. SAM inhibits ODC activity and H-RAS, K-RAS, c-MYC expression. Through the inhibition of LKB1/AMPK axis, SAM controls p53 phosphorylation and cell growth and survival by inducing PP2A expression that dephosphorylating inactivates AKT. Moreover, PP2A activation and DUSP1 stabilization inhibit the RAS/ERK pathway. DUSP1 phosphorylation at the ser296, induced by the ERK1/2 target FOXM1, allows its ubiquitination by the SKP2/CKS1 ubiquitin ligase. This is followed by the proteasomal degradation of DUSP1. SAM enhances the DUSP1 inhibitory action by increasing the transcription of DUSP1 mRNA and by inhibiting the DUSP1 proteasomal degradation. The inhibition of LKB1/AMPK decreases eNOS and iNOS activity and ROS and NO, and thus the genomic instability that is also reduced by the decrease of DNA hypomethylation.
Figure 5
Figure 5
Multiphasic hepatocarcinogenesis. Retro-reverse arrows indicate remodeling. Arrows thickness is proportional to the rate and intensity of the changes. Abbreviations: DN, dysplastic nodules; FAH, foci of altered hepatocytes; HCC, hepatocellular carcinomas.
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