Abstract
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.
Footnotes
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This work was supported by the National Institutes of Health National Center for Complementary and Alternative Medicine [Grant AT004896] and by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grants DK44510, DK48522].
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ABBREVIATIONS: SAMe, S-adenosylmethionine; 5-FU, 5-fluorouracil; cFLIP, cellular FLICE inhibitory protein; cFLIPL, cellular FLICE inhibitory protein-long; cFLIPS, cellular FLICE inhibitory protein-short; DISC, death-inducing signaling complex; BIRC7, baculoviral inhibitor of apoptosis repeat-containing 7; BFAR, bifunctional apoptosis regulator; FBS, fetal bovine serum; IGF, insulin-like growth factor; MAT, methionine adenosyltransferase; MTA, methylthioadenosine; PCR, polymerase chain reaction; rTRAIL, recombinant tumor necrosis factor α-related apoptosis-inducing ligand; TNFα, tumor necrosis factor-α; TRAIL, tumor necrosis factor-α-related apoptosis-inducing ligand; CFLAR, caspase-8 and Fas-associated protein with death domain-like apoptosis regulator; DMSO, CPT-11, irinotecan.
- Accepted April 15, 2009.
- Received December 22, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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