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.