S-Adenosylmethionine in cell growth, apoptosis and liver cancer.
S-Adenosylmethionine (SAMe), the principal biological methyl donor, is synthesized from methionine and ATP in a reaction catalyzed by methionine adenosyltransferase (MAT). In mammals, two genes (MAT1A and MAT2A), encode for two homologous MAT catalytic subunits, while a third gene MAT2beta, encodes for the beta-subunit that regulates MAT2A-encoded isoenzyme. Normal liver expresses MAT1A, whereas extrahepatic tissues express MAT2A. MAT2A and MAT2 beta are induced in human hepatocellular carcinoma (HCC), which facilitate cancer cell growth. Patients with cirrhosis of various etiologies, including alcohol, have decreased hepatic MAT activity and SAMe biosynthesis. Consequences of hepatic SAMe deficiency as illustrated by the Mat1a knock-out mouse model include increased susceptibility to steatosis and oxidative liver injury, spontaneous development of steatohepatitis and HCC. Predisposition to HCC can be partly explained by the effect of SAMe on growth. Thus, SAMe inhibits the mitogenic effect of growth factors such as hepatocyte growth factor and, following partial hepatectomy, a fall in SAMe level is required for the liver to regenerate. During liver regeneration, the fall in hepatic SAMe is transient. If the fall were to persist, it would favor a proliferative phenotype and, ultimately, development of HCC. Not only does SAMe control liver growth, it also regulates apoptosis. Interestingly, SAMe is anti-apoptotic in normal hepatocytes but pro-apoptotic in liver cancer cells. In liver cancer cells but not in normal human hepatocytes, SAMe can selectively induce Bcl-x(S), an alternatively spliced isoform of Bcl-x(L) that promotes apoptosis. This should make SAMe an attractive agent for both chemoprevention and treatment of HCC.
Lu
Shelly C
SC
Division of Gastroenterology and Liver Diseases, USC Research Center for Liver Diseases, Keck School of Medicine USC, Los Angeles, California 90033, USA. shellylu@hsc.usc.edu
Mato
José M
JM
D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000473:pathology*; D049109:Cell Proliferation; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology* / Q000473:pathology*; D012436:S-Adenosylmethionine / Q000502:physiology*
D012436:S-Adenosylmethionine