PT  - JOURNAL ARTICLE
AU  - Tony W. H. Li
AU  - Qingsong Zhang
AU  - Pilsoo Oh
AU  - Meng Xia
AU  - Hui Chen
AU  - Sean Bemanian
AU  - Natalie Lastra
AU  - Magda Circ
AU  - Mary Pat Moyer
AU  - José M. Mato
AU  - Tak Yee Aw
AU  - Shelly C. Lu
TI  - <em>S</em>-Adenosylmethionine and Methylthioadenosine Inhibit Cellular FLICE Inhibitory Protein Expression and Induce Apoptosis in Colon Cancer Cells
AID  - 10.1124/mol.108.054411
DP  - 2009 Jul 01
TA  - Molecular Pharmacology
PG  - 192--200
VI  - 76
IP  - 1
4099  - http://molpharm.aspetjournals.org/content/76/1/192.short
4100  - http://molpharm.aspetjournals.org/content/76/1/192.full
SO  - Mol Pharmacol2009 Jul 01; 76
AB  - S-Adenosylmethionine (SAMe) and its metabolite 5′-methylthioadenosine (MTA) inhibit mitogen-induced proliferative response in liver and colon cancer cells. SAMe and MTA are also proapoptotic in liver cancer cells by selectively inducing Bcl-xS expression. The aims of this work were to assess whether these agents are proapoptotic in colon cancer cells, and if so, to elucidate the molecular mechanisms. We found that both SAMe and MTA are proapoptotic in HT-29 and RKO cells in a dose- and time-dependent manner. Gene microarray uncovered down-regulation of cellular FLICE inhibitory protein (cFLIP). SAMe and MTA treatment led to a decrease in the mRNA and protein levels of both the long and short cFLIP isoforms. This required de novo RNA synthesis and was associated with activation of procaspase-8, Bid cleavage, and release of cytochrome c from the mitochondria. Inhibiting caspase 8 activity or overexpression of cFLIP protected against apoptosis, whereas supplementing with polyamines did not. SAMe and MTA treatment sensitized RKO cells to tumor necrosis factor α-related apoptosis-inducing ligand-induced apoptosis. Although SAMe and MTA are proapoptotic in colon cancer cells, they have no toxic effects in NCM460 cells, a normal colon epithelial cell line. In contrast to liver cancer cells, SAMe and MTA had no effect on Bcl-xS expression in colon cancer cells. In conclusion, SAMe and MTA are proapoptotic in colon cancer cells but not normal colon epithelial cells. One molecular mechanism identified is the inhibition of cFLIP expression. SAMe and MTA may be attractive agents in the chemoprevention and treatment of colon cancer.