Diminished S-adenosylmethionine biosynthesis and its metabolism in a model of hepatocellular carcinoma is recuperated by an adenosine derivative

Abstract

S-adenosylmethionine (SAM), biosynthesis from methionine and ATP, is markedly decreased in hepatocellularular carcinoma (HCC) for a diminution in ATP levels, and the down regulation of the liver specific MAT1a enzyme. Its metabolic activity is very important in the transmethylation reactions, the methionine cycle, the biosynthesis of glutathione (GSH) and the polyamine pathway, which are markedly affected in the HCC. The chemo-preventive effect of IFC305 in HCC induced by DEN, and the increase of ATP and SAM in CCl 4-induced cirrhosis have been previously demonstrated. The aim of this work was to test whether this chemopreventive effect is mediated by the induction of SAM biosynthesis and its metabolic flow. SAM hepatic levels and the methionine cycle were recovered with IFC305 treatment, restoring transmethylation and transsulfuration activities. IFC305 treatment, increased MAT1a levels and decrease MAT2a levels through modulation of their post-transcriptional regulation. This occurred through the binding of the AUF1 (binding factor 1 AU-rich sites) and HuR (human antigen R) ribonucleoproteins to Mat1a and Mat2a messenger RNAs, which maintained their nuclear localization. Finally, the compound inhibited the polyamine pathway favoring the recuperation of the normal methionine and one carbon cycle recuperating the metabolic flow of methionine, which probably facilitated its HCC chemo-preventive effect.

Methionine metabolism in chronic liver diseases: an update on molecular mechanism and therapeutic implication

“…129 Exogenous SAM can inhibit HCC development by recovering the normal level of SAM. 131 However, 24-day intravenous infusion of SAM did not affect the size of the formed tumors, which may be due to the compensatory induction of GNMT, and prevented SAM accumulation. 38 A study revealed that tumor-initiating cells become addicted to exogenous methionine because of highly elevated methionine cycle activity.…”

“… 129 , 130 During the general development of the fetal liver, the originally expressed MAT2A is gradually replaced by MAT1A. 116 , 131 MAT2A and its gene product, MAT IIα (dimer formed from α2 subunits), are overexpressed in various human epithelial tumors. TNF-α upregulates MAT2A via NF-κB and adaptor-related protein complex 1.…”

Milk Metabolomics Reveals Potential Biomarkers for Early Prediction of Pregnancy in Buffaloes Having Undergone Artificial Insemination

“…5 -O-{[3-({4-[(3Aminopropyl)amino]butyl}amino)propyl]carbamoyl}-2 -deoxyadenosine is an adenosine derivative. Adenosine, an essential metabolite distributed in several mammalian tissues [57,58], acts as a ubiquitous endogenous cell signaling and modulator agent since it directly affects a variety of synaptic processes and signaling pathways, thus playing an important role in the regulation of several neurotransmitters in the central nervous system [59]. Moreover, adenosine produced in hypoxic, ischemic, or inflamed environments reduces tissue injury and promotes repair [60].…”

mRNA Post-Transcriptional Regulation by AU-Rich Element-Binding Proteins in Liver Inflammation and Cancer

“…Finally, the two AUBPs AUF1 and HuR have been found to deeply impact the amino acid metabolism in the liver of rats treated with the carcinogen DEN. The levels of S-adenosylmethionine (SAM) were indeed decreased by the activity of these two AUBPs, which regulate the gene expression of methionine adenosyltransferase 1a and 2a ( Mat1a and Mat2a ) [ 176 ]. Of importance, a metabolic switch from Mat1a to Mat2a expression, which translates into the downregulation of SAM levels, is a well-known metabolic reprogramming event favoring HCC progression.…”