title: Role of methionine adenosyltransferase 2A and S-adenosylmethionine in mitogen-induced growth of human colon cancer cells.
abstract: OBJECTIVE
  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.
authors.affiliation: Division of Gastroenterology and Liver Diseases, University of Southern California Research Center for Liver Diseases, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.forename: Meng
authors.initials: M
authors.lastname: Xia
authors.forename: Mark
authors.initials: M
authors.lastname: Lin
authors.forename: Heping
authors.initials: H
authors.lastname: Yang
authors.forename: John
authors.initials: J
authors.lastname: Kuhlenkamp
authors.forename: Tony
authors.initials: T
authors.lastname: Li
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Sodir
authors.forename: Yong-Heng
authors.initials: YH
authors.lastname: Chen
authors.forename: Heinz
authors.initials: H
authors.lastname: Josef-Lenz
authors.forename: Peter W
authors.initials: PW
authors.lastname: Laird
authors.forename: Steven
authors.initials: S
authors.lastname: Clarke
authors.forename: José M
authors.initials: JM
authors.lastname: Mato
authors.forename: Shelly C
authors.initials: SC
authors.lastname: Lu
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives; D000368:Aged; D000818:Animals; D016923:Cell Death; D002455:Cell Division; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D004347:Drug Interactions; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007417:Intestinal Polyps / Q000235:genetics / Q000378:metabolism; D020738:Leptin / Q000494:pharmacology; D008297:Male; D008716:Methionine Adenosyltransferase / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D008934:Mitogens / Q000494:pharmacology; D011073:Polyamines / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D012436:S-Adenosylmethionine / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D020738:Leptin; D008934:Mitogens; D011073:Polyamines; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D012436:S-Adenosylmethionine; D008716:Methionine Adenosyltransferase; D000241:Adenosine