Role of methionine adenosyltransferase 2A and S-adenosylmethionine in mitogen-induced growth of human colon cancer cells.

BACKGROUND & AIMS Two genes (MAT1A and MAT2A) encode for methionine adenosyltransferase, an essential enzyme responsible for S-adenosylmethionine (SAMe) biosynthesis. MAT1A is expressed in liver, whereas MAT2A is widely distributed. In liver, increased MAT2A expression is associated with growth, while SAMe inhibits MAT2A expression and growth. The role of MAT2A in colon cancer in unknown. The aims of this study were to examine whether MAT2A expression and SAMe and its metabolite methylthioadenosine (MTA) can modulate growth of colon cancer cells. METHODS Studies were conducted using resected colon cancer specimens, polyps from Min mice, and human colon cancer cell lines RKO and HT-29. MAT2A expression was measured by real-time polymerase chain reaction and cell growth by the 3-(4,5-dimethylthiazolyl-2-yl)-2,5-diphenyltetrazolium bromide assay. RESULTS In 12 of 13 patients and all 9 polyps from Min mice, the MAT2A messenger RNA levels were 200%-340% of levels in adjacent normal tissues, respectively. Epidermal growth factor, insulin-like growth factor 1, and leptin increased growth and up-regulated MAT2A expression and MAT2A promoter activity in RKO and HT-29 cells. SAMe and MTA lowered the baseline expression of MAT2A and blocked the growth factor-mediated increase in MAT2A expression and growth in colon cancer cell lines. Importantly, the mitogenic effect of these growth factors was inhibited if MAT2A induction was prevented by RNA interference. SAMe and MTA supplementation in drinking water increased intestinal SAMe levels and lowered MAT2A expression. CONCLUSIONS Similar to the liver, up-regulation of MAT2A also provides a growth advantage and SAMe and MTA can block mitogenic signaling in colon cancer cells.

[1]  M. Avila,et al.  S‐Adenosylmethionine regulates MAT1A and MAT2A gene expression in cultured rat hepatocytes: a new role for S‐adenosylmethionine in the maintenance of the differentiated status of the liver , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[2]  Young-In Kim.  Role of folate in colon cancer development and progression. , 2003, The Journal of nutrition.

[3]  S. Clarke.  16 Inhibition of mammalian protein methyltransferases by 5'-methylthioadenosine (MTA): A mechanism of action of dietary same? , 2006, The Enzymes.

[4]  Shelly C. Lu,et al.  Hepatocyte growth factor induces MAT2A expression and histone acetylation in rat hepatocytes: role in liver regeneration 1 , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[5]  Shelly C. Lu,et al.  Spontaneous oxidative stress and liver tumors in mice lacking methionine adenosyltransferase 1A , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[6]  P. Stattin,et al.  Obesity and colon cancer: Does leptin provide a link? , 2004, International journal of cancer.

[7]  M. Kay Washington,et al.  Importance of epidermal growth factor receptor signaling in establishment of adenomas and maintenance of carcinomas during intestinal tumorigenesis , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[8]  Shelly C. Lu,et al.  Differential expression of methionine adenosyltransferase genes influences the rate of growth of human hepatocellular carcinoma cells. , 1998, Cancer research.

[9]  A. Feinberg,et al.  The history of cancer epigenetics , 2004, Nature Reviews Cancer.

[10]  Do-Hyun Nam,et al.  Dual inhibition of epidermal growth factor receptor and vascular endothelial growth factor receptor phosphorylation by AEE788 reduces growth and metastasis of human colon carcinoma in an orthotopic nude mouse model. , 2005, Cancer research.

[11]  J. Whaun,et al.  Femtomolar ion-pair high-performance liquid chromatographic method for determining Dns-polyamine derivatives of red blood cell extracts utilizing an automated polyamine analyzer. , 1982, Journal of chromatography.

[12]  Shelly C. Lu,et al.  S-adenosylmethionine regulates cytoplasmic HuR via AMP-activated kinase. , 2006, Gastroenterology.

[13]  E. Rimm,et al.  Alcohol, low-methionine--low-folate diets, and risk of colon cancer in men. , 1995, Journal of the National Cancer Institute.

[14]  L. Ellis,et al.  Impact of Insulin-Like Growth Factor Receptor-I Function on Angiogenesis, Growth, and Metastasis of Colon Cancer , 2002, Laboratory Investigation.

[15]  Shelly C. Lu,et al.  Cloning and characterization of the human glutathione synthetase 5'-flanking region. , 2005, The Biochemical journal.

[16]  Shelly C. Lu,et al.  Role of methionine adenosyltransferase and S-adenosylmethionine in alcohol-associated liver cancer. , 2005, Alcohol.

[17]  Shelly C. Lu,et al.  Induction of Human Methionine Adenosyltransferase 2A Expression by Tumor Necrosis Factor α , 2003, Journal of Biological Chemistry.

[18]  R. Weinberg,et al.  Suppression of intestinal neoplasia by DNA hypomethylation , 1995, Cell.

[19]  M. Mareel,et al.  Leptin promotes invasiveness of kidney and colonic epithelial cells via phosphoinositide 3‐kinase‐, Rho‐, and Rac‐dependent signaling pathways , 2000, The FASEB Journal.

[20]  J. Hwang,et al.  Changes in S‐adenosylmethionine synthetase in human liver cancer: Molecular characterization and significance , 1996, Hepatology.

[21]  Shelly C. Lu,et al.  The role of c‐Myb and Sp1 in the up‐regulation of methionine adenosyltransferase 2A gene expression in human hepatocellular carcinoma , 2001 .

[22]  Shelly C. Lu,et al.  S‐adenosylmethionine and methylthioadenosine are antiapoptotic in cultured rat hepatocytes but proapoptotic in human hepatoma cells , 2002, Hepatology.

[23]  S. Alemany,et al.  Interleukin-2 induces gamma-S-adenosyl-L-methionine synthetase gene expression during T-lymphocyte activation. , 1996, The Biochemical journal.

[24]  L. Gaspa,et al.  Comparative effects of L-methionine, S-adenosyl-L-methionine and 5'-methylthioadenosine on the growth of preneoplastic lesions and DNA methylation in rat liver during the early stages of hepatocarcinogenesis. , 1991, Anticancer research.

[25]  Shelly C. Lu,et al.  Changes in methionine adenosyltransferase during liver regeneration in the rat. , 1998, American journal of physiology. Gastrointestinal and liver physiology.

[26]  P. Laird,et al.  Smad3 deficiency promotes tumorigenesis in the distal colon of ApcMin/+ mice. , 2006, Cancer research.

[27]  M. Kotb,et al.  Expression and Functional Interaction of the Catalytic and Regulatory Subunits of Human Methionine Adenosyltransferase in Mammalian Cells* , 1999, The Journal of Biological Chemistry.

[28]  P. Fortes,et al.  Methionine adenosyltransferase II beta subunit gene expression provides a proliferative advantage in human hepatoma. , 2003, Gastroenterology.

[29]  S. Deventer,et al.  Leptin is a growth factor for colonic epithelial cells. , 2001, Gastroenterology.

[30]  Shelly C. Lu,et al.  Inhibition of lipopolysaccharide-stimulated TNF-α promoter activity by S-adenosylmethionine and 5′-methylthioadenosine , 2004 .

[31]  B. Decallonne,et al.  An overview of real-time quantitative PCR: applications to quantify cytokine gene expression. , 2001, Methods.

[32]  F. Speleman,et al.  Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes , 2002, Genome Biology.

[33]  H. Yang,et al.  Role of promoter methylation in increased methionine adenosyltransferase 2A expression in human liver cancer. , 2001, American journal of physiology. Gastrointestinal and liver physiology.

[34]  A. Niveleau,et al.  Effects of 5'deoxy-5'-methylthioadenosine on the metabolism of S-adenosyl methionine. , 1983, Biochemical and biophysical research communications.

[35]  Shelly C. Lu,et al.  S‐adenosylmethionine and its metabolite induce apoptosis in HepG2 cells: Role of protein phosphatase 1 and Bcl‐xS , 2004, Hepatology.

[36]  S. Clarke,et al.  Altered Levels of S-Adenosylmethionine and S-Adenosylhomocysteine in the Brains ofl-Isoaspartyl (d-Aspartyl)O-Methyltransferase-deficient Mice* , 2002, The Journal of Biological Chemistry.

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