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 to 75%, increased apoptosis and inhibited growth. Putrescine supplementation blunted significantly MAT2A siRNA-induced apoptosis and growth suppression. Putrescine treatment (100 pmol/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.

Methionine adenosyltransferase α2 sumoylation positively regulate Bcl-2 expression in human colon and liver cancer cells

“…We previously reported that treatment with SAMe and its metabolite MTA induced apoptosis in HepG2 and RKO cells [ 19 , 20 ] and lowered Ubc9 protein stability [ 10 ]. Ubc9 has been shown to regulate apoptosis as a positive regulator of Bcl-2 expression in breast cancer MCF-7 cells [ 14 ].…”

“…Bcl-2 protein has well-known anti-apoptotic functions [ 21 , 22 ]. In addition to lowering Ubc9 and Bcl-2 expression, SAMe and MTA treatment also lowered MAT2A expression [ 20 ] and knockdown of MAT2A in HepG2 and RKO cells induced apoptosis [ 17 , 19 ]. These observations prompted us to examine whether there is interplay between MAT2A, Ubc9 and Bcl2.…”

“…MAT1A encodes for α1 that forms dimer (MATIII) and tetramer (MATI) that are predominantly expressed in liver parenchymal cells; while MAT2A encodes the α2 catalytic subunit of the MATII isoenzyme that is expressed in all other tissues [ 16 ]. Human liver and colon cancers have higher MAT2A expression [ 17 – 19 ], which is essential for growth as silencing MAT2A by sequence-specific small interfering RNA (siRNA) inhibited growth and induced apoptosis [ 19 , 20 ]. We reported that SAMe treatment lowered Ubc9 protein expression and sumoylation in liver, colon and breast cancer cell lines [ 10 ].…”

A novel mechanism of the M1‐M2 methionine adenosyltransferase switch‐mediated hepatocellular carcinoma metastasis

“…Most publications have focused on the regulatory function of MAT1A or MAT2A in cell proliferation and death . Yang et al showed that knockdown of MAT1A promoted metastasis of HepG2 cells in an orthotopic liver implantation model.…”

“…Taken together, these data elucidate the pleiotropic effects of MAT deregulation in progression and prognosis of liver cancer 31. Most publications have focused on the regulatory function of MAT1A or MAT2A in cell proliferation and death 5,13,32,33. Yang et al17 showed that knockdown of MAT1A promoted metastasis of HepG2…”