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

Authors
  • Lozano-Rosas, María Guadalupe1
  • Chávez, Enrique1
  • Velasco-Loyden, Gabriela1
  • Domínguez-López, Mariana1
  • Martínez-Pérez, Lidia1
  • Chagoya De Sánchez, Victoria1
  • 1 Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico. , (Mexico)
Type
Published Article
Journal
Cancer Biology & Therapy
Publisher
Landes Bioscience
Publication Date
Jan 01, 2020
Volume
21
Issue
1
Pages
81–94
Identifiers
DOI: 10.1080/15384047.2019.1665954
PMID: 31552788
Source
Medline
Keywords
Language
English
License
Unknown

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 CCl4-induced cirrhosis have been previously demonstrated. The aim of this work was to test whether this chemo-preventive 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.

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