S-Adenosylmethionine and methylthioadenosine inhibit cellular FLICE inhibitory protein expression and induce apoptosis in colon cancer cells.
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.
Li
Tony W H
TW
Division of Gastroenterology and Liver Diseases, University of Southern California Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Zhang
Qingsong
Q
Oh
Pilsoo
P
Xia
Meng
M
Chen
Hui
H
Bemanian
Sean
S
Lastra
Natalie
N
Circ
Magda
M
Moyer
Mary Pat
MP
Mato
José M
JM
Aw
Tak Yee
TY
Lu
Shelly C
SC
D017209:Apoptosis / Q000187:drug effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000037:antagonists & inhibitors* / Q000502:physiology; D053181:Caspase 8 / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D003839:Deoxyadenosines / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D012436:S-Adenosylmethionine / Q000494:pharmacology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D013872:Thionucleosides / Q000494:pharmacology*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D003839:Deoxyadenosines; D053221:TNF-Related Apoptosis-Inducing Ligand; D013872:Thionucleosides; C008500:5'-methylthioadenosine; D012436:S-Adenosylmethionine; D045304:Cytochromes c; D003513:Cycloheximide; D053181:Caspase 8