Carcinoma Cells Genes Influences the Rate of Growth of Human Hepatocellular Differential Expression of Methionine Adenosyltransferase Updated

Methionine adenosyltransferase (MAT) catalyzes the formation of V adenos.vlmethionine (SAM), the principal methyl donor, and is essential to normal cell function. The two forms of MAT, liver specific and non-liver specific, are products of two genes, MATI A and MAT2A, respectively. We have reported a switch from MATI A to MAT2A gene expression in human liver cancer cells. In the current work, we examined whether the type of MAT expressed by the cell influences cell growth. Ilui 1-7 cells were stably transfected with MATI A and were subsequently treated with antisense oligonucleotides directed against MAT2A. MAT2A antisense treatment reduced the amount of MAT2A mRNA by 99% but had no effect on MATI A mRNA. Cell growth and DNA synthesis rates were reduced by -20-25% after transfection with MAT1A and by an additional 30-40% after MAT2A antisense treatment. SAM level and SAM:S-adenosylhomocysteine (SAH) ratio increased by 50-75% after MA TÃŒA transfection and by an additional 60-80% after MAT2A antisense treatment. DNA methylation changed in parallel to changes in SAM level and S \\I:S \11 ratio. Supplementing untransfected HuH-7 cells with SAM in the culture me dium increased SAM level, SAM:S Ml ratio, and DNA methylation and decreased cell growth and DNA synthesis. In conclusion, cell growth is influenced by the type of MAT expressed. The mechanism likely involves changes in S \M:S VII ratio and DNA methylation.

[1]  B. P. Doctor,et al.  S-Adenosylmethionine and methylation , 2020 .

[2]  M. Pajares,et al.  Glucocorticoid Regulation of Hepatic S-Adenosylmethionine Synthetase Gene Expression * , 1997 .

[3]  M. Kotb,et al.  Consensus nomenclature for the mammalian methionine adenosyltransferase genes and gene products. , 1997, Trends in genetics : TIG.

[4]  J. Viña,et al.  Increased sensitivity to oxidative injury in chinese hamster ovary cells stably transfected with rat liver S-adenosylmethionine synthetase cDNA. , 1996, The Biochemical journal.

[5]  G. Farrell,et al.  Effects of extracellular Ca2+ and HCO3- on epidermal growth factor-induced DNA synthesis in cultured rat hepatocytes. , 1995, Gastroenterology.

[6]  L. Gaspa,et al.  Correlation between S-adenosyl-L-methionine content and production of c-myc, c-Ha-ras, and c-Ki-ras mRNA transcripts in the early stages of rat liver carcinogenesis. , 1994, Cancer letters.

[7]  K. Tsukada,et al.  Immunohistochemical analysis of rat S‐adenosylmethionine synthetase isozymes in developmental liver , 1993, FEBS letters.

[8]  M. Pajares,et al.  Modulation of rat liver S-adenosylmethionine synthetase activity by glutathione. , 1992, The Journal of biological chemistry.

[9]  L. Poirier,et al.  Methyl groups in carcinogenesis: effects on DNA methylation and gene expression. , 1992, Cancer research.

[10]  S. Freier,et al.  Antisense oligonucleotides inhibit intercellular adhesion molecule 1 expression by two distinct mechanisms. , 1991, The Journal of biological chemistry.

[11]  K. Tsukada,et al.  Molecular cloning and nucleotide sequence of cDNA encoding the human liver S-adenosylmethionine synthetase. , 1991, Biochemistry international.

[12]  G. Satta,et al.  Reversal by 5-azacytidine of the S-adenosyl-L-methionine-induced inhibition of the development of putative preneoplastic foci in rat liver carcinogenesis. , 1991, Cancer letters.

[13]  J. Finkelstein,et al.  Methionine metabolism in mammals. , 1990, The Journal of nutritional biochemistry.

[14]  S. Alemany,et al.  Specific loss of the high‐molecular‐weight form of S‐adenosyl‐L‐methionine synthetase in human liver cirrhosis , 1988, Hepatology.

[15]  M. Kotb,et al.  Methionine adenosyltransferase and S-adenosylmethionine in the developing rat lens. , 1988, Experimental eye research.

[16]  L. Poirier,et al.  c-H-ras and c-K-ras gene hypomethylation in the livers and hepatomas of rats fed methyl-deficient, amino acid-defined diets. , 1988, Carcinogenesis.

[17]  S. Alemany,et al.  Purification and comparison of two forms of S-adenosyl-L-methionine synthetase from rat liver. , 1987, European journal of biochemistry.

[18]  L. Gaspa,et al.  Variations of ornithine decarboxylase activity and S-adenosyl-L-methionine and 5'-methylthioadenosine contents during the development of diethylnitrosamine-induced liver hyperplastic nodules and hepatocellular carcinoma. , 1987, Carcinogenesis.

[19]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[20]  L. Pirisi,et al.  The Variations of S-adenosyl-L-methionine Content Modulate Hepatocyte Growth During Phenobarbital Promotion of Diethylnitrosamine-Induced Rat Liver Carcinogenesis , 1987, Toxicologic pathology.

[21]  J. Finkelstein,et al.  Methionine metabolism in mammals. Adaptation to methionine excess. , 1986, The Journal of biological chemistry.

[22]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[23]  D. Rowitch,et al.  Extent of DNA methylation in human tumor cells. , 1983, Journal of the National Cancer Institute.

[24]  D. Sullivan,et al.  Fractionation and kinetic properties of rat liver and kidney methionine adenosyltransferase isozymes. , 1983, Biochemistry.

[25]  J. Sufrin,et al.  Differences in the active-site region of tumor versus normal isozymes of mammalian ATP:L-methionine S-adenosyltransferase. , 1982, Molecular pharmacology.

[26]  H. Teraoka,et al.  Multiple species of mammalian S-adenosylmethionine synthetase. Partial purification and characterization. , 1981, Biochemistry.

[27]  C. F. Chang,et al.  Correlation of isozyme patterns of S-adenosylmethionine synthetase with fetal stages and pathological states of the liver. , 1979, Cancer research.

[28]  M. M. Bradford.  A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. , 1976, Analytical biochemistry.

[29]  D. Russell,et al.  Polyamines. (1) Enhanced s-adenosyl-L-methionine decarboxylase in rapid growth systems, and (2) the relationships between polyamine concentration and RNA accumulation. , 1971, Biochimica et biophysica acta.