title: Polyamine and methionine adenosyltransferase 2A crosstalk in human colon and liver cancer.
abstract: Methionine adenosyltransferase (MAT) is an essential enzyme that is responsible for the biosynthesis of S-adenosylmethionine (SAMe), the principal methyl donor and precursor of polyamines. MAT1A is expressed in normal liver and MAT2A is expressed in all extrahepatic tissues. MAT2A expression is increased in human colon cancer and in colon cancer cells treated with mitogens, whereas silencing MAT2A resulted in apoptosis. The aim of the current work was to examine the mechanism responsible for MAT2A-dependent growth and apoptosis. We found that in RKO (human adenocarcinoma cell line) cells, MAT2A siRNA treatment lowered cellular SAMe and putrescine levels by 70-75%, increased apoptosis and inhibited growth. Putrescine supplementation blunted significantly MAT2A siRNA-induced apoptosis and growth suppression. Putrescine treatment (100pmol/L) raised MAT2A mRNA level to 4.3-fold of control, increased the expression of c-Jun and c-Fos and binding to an AP-1 site in the human MAT2A promoter and the promoter activity. In human colon cancer specimens, the expression levels of MAT2A, ornithine decarboxylase (ODC), c-Jun and c-Fos are all elevated as compared to adjacent non-tumorous tissues. Overexpression of ODC in RKO cells also raised MAT2A mRNA level and MAT2A promoter activity. ODC and MAT2A are also overexpressed in liver cancer and consistently, similar MAT2A-ODC-putrescine interactions and effects on growth and apoptosis were observed in HepG2 cells. In conclusion, there is a crosstalk between polyamines and MAT2A. Increased MAT2A expression provides more SAMe for polyamines biosynthesis; increased polyamine (putrescine in this case) can activate MAT2A at the transcriptional level. This along with increased ODC expression in cancer all feed forward to further enhance the proliferative capacity of the cancer cell.
authors.affiliation: Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA; USC Research Center for Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA; The Southern California Research Center for Alcoholic and Pancreatic Diseases & Cirrhosis, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Maria Lauda
authors.initials: ML
authors.lastname: Tomasi
authors.affiliation: Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA; USC Research Center for Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Minjung
authors.initials: M
authors.lastname: Ryoo
authors.affiliation: Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA; USC Research Center for Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Skay
authors.affiliation: Department of Colorectal Surgery, Whipps Cross University Hospital, London E11 1NR, UK.
authors.forename: Ivan
authors.initials: I
authors.lastname: Tomasi
authors.affiliation: Department of Colorectal Surgery, Whipps Cross University Hospital, London E11 1NR, UK.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Giordano
authors.affiliation: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, 48160 Derio, Bizkaia, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Mato
authors.affiliation: Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA; USC Research Center for Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA; The Southern California Research Center for Alcoholic and Pancreatic Diseases & Cirrhosis, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA. Electronic address: shellylu@usc.edu.
authors.forename: Shelly C
authors.initials: SC
authors.lastname: Lu
mesh_terms: D000368:Aged; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000201:enzymology / Q000378:metabolism*; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008716:Methionine Adenosyltransferase / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009955:Ornithine Decarboxylase / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D011700:Putrescine / Q000378:metabolism*; D034741:RNA, Small Interfering; D012436:S-Adenosylmethionine / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D012436:S-Adenosylmethionine; C527161:MAT2A protein, human; D008716:Methionine Adenosyltransferase; D009955:Ornithine Decarboxylase; D011700:Putrescine