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-x(S) 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 alpha-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-x(S) 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.