QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.108.054411v1 76/1/192    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Li, T. W. H. Articles by Lu, S. C. PubMed PubMed Citation Articles by Li, T. W. H. Articles by Lu, S. C.

S-Adenosylmethionine and Methylthioadenosine Inhibit Cellular FLICE Inhibitory Protein Expression and Induce Apoptosis in Colon Cancer Cells

Division of Gastroenterology and Liver Diseases, University of Southern California Research Center for Liver Diseases, University of Southern California-University of California Los Angeles Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California (T.W.H.L., Q.Z., P.O., M.X., H.C., S.B., N.L., S.C.L.); Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana (M.C., T.Y.A.); and INCELL Corporation, San Antonio, Texas (M.P.M.); and CIC bioGUNE, Ciberehd, Bizkaia, Spain (J.M.M.)

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 -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.

Received for publication December 22, 2008.

Accepted for publication April 15, 2009.

Address correspondence to: Dr. Shelly C. Lu, Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, USC, HMR Bldg. 415, 2011 Zonal Ave., Los Angeles, CA 90033. E-mail: shellylu{at}usc.edu