title: S-Adenosylmethionine and methylthioadenosine inhibit β-catenin signaling by multiple mechanisms in liver and colon cancer.
abstract: S-Adenosylmethionine (SAMe), the principal methyl donor that is available as a nutritional supplement, and its metabolite methylthioadenosine (MTA) exert chemopreventive properties against liver and colon cancer in experimental models. Both agents reduced β-catenin expression on immunohistochemistry in a murine colitis-associated colon cancer model. In this study, we examined the molecular mechanisms involved. SAMe or MTA treatment in the colitis-associated cancer model lowered total β-catenin protein levels by 47 and 78%, respectively. In an orthotopic liver cancer model, increasing SAMe levels by overexpressing methionine adenosyltransferase 1A also reduced total β-catenin levels by 68%. In both cases, lower cyclin D1 and c-Myc expression correlated with lower β-catenin levels. In liver (HepG2) and colon (SW480, HCT116) cancer cells with constitutively active β-catenin signaling, SAMe and MTA treatment inhibited β-catenin activity by excluding it from the nuclear compartment. However, in liver (Huh-7) and colon (RKO) cancer cells expressing wild-type Wnt/β-catenin, SAMe and MTA accelerated β-catenin degradation by a glycogen synthase kinase 3-β-dependent mechanism. Both agents lowered protein kinase B activity, but this was not mediated by inhibiting phosphoinositide 3-kinase. Instead, both agents increased the activity of protein phosphatase 2A, which inactivates protein kinase B. The effect of MTA on lowering β-catenin is direct and not mediated by its conversion to SAMe, as blocking this conversion had no influence. In conclusion, SAMe and MTA inhibit Wnt/β-catenin signaling in colon and liver cancer cells regardless of whether this pathway is aberrantly induced, making them ideal candidates for chemoprevention and/or chemotherapy in these cancers.
authors.affiliation: Division of Gastroenterology, Cedars Sinai Medical Center, Los Angeles, California (T.W.H.L., H.P., H.Y., S.C.L.); University of Southern California Research Center for Liver Diseases, Keck School of Medicine, Los Angeles, California (T.W.H.L., H.P., H.Y., S.K., P.P., S.C.L.); Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital Los Angeles, Los Angeles, California (Y.Z.); and CIC bioGUNE, Ciberehd, Bizkaia, Spain (J.M.M.).
authors.forename: Tony W H
authors.initials: TW
authors.lastname: Li
authors.affiliation: Division of Gastroenterology, Cedars Sinai Medical Center, Los Angeles, California (T.W.H.L., H.P., H.Y., S.C.L.); University of Southern California Research Center for Liver Diseases, Keck School of Medicine, Los Angeles, California (T.W.H.L., H.P., H.Y., S.K., P.P., S.C.L.); Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital Los Angeles, Los Angeles, California (Y.Z.); and CIC bioGUNE, Ciberehd, Bizkaia, Spain (J.M.M.).
authors.forename: Hui
authors.initials: H
authors.lastname: Peng
authors.affiliation: Division of Gastroenterology, Cedars Sinai Medical Center, Los Angeles, California (T.W.H.L., H.P., H.Y., S.C.L.); University of Southern California Research Center for Liver Diseases, Keck School of Medicine, Los Angeles, California (T.W.H.L., H.P., H.Y., S.K., P.P., S.C.L.); Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital Los Angeles, Los Angeles, California (Y.Z.); and CIC bioGUNE, Ciberehd, Bizkaia, Spain (J.M.M.).
authors.forename: Heping
authors.initials: H
authors.lastname: Yang
authors.affiliation: Division of Gastroenterology, Cedars Sinai Medical Center, Los Angeles, California (T.W.H.L., H.P., H.Y., S.C.L.); University of Southern California Research Center for Liver Diseases, Keck School of Medicine, Los Angeles, California (T.W.H.L., H.P., H.Y., S.K., P.P., S.C.L.); Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital Los Angeles, Los Angeles, California (Y.Z.); and CIC bioGUNE, Ciberehd, Bizkaia, Spain (J.M.M.).
authors.forename: Steven
authors.initials: S
authors.lastname: Kurniawidjaja
authors.affiliation: Division of Gastroenterology, Cedars Sinai Medical Center, Los Angeles, California (T.W.H.L., H.P., H.Y., S.C.L.); University of Southern California Research Center for Liver Diseases, Keck School of Medicine, Los Angeles, California (T.W.H.L., H.P., H.Y., S.K., P.P., S.C.L.); Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital Los Angeles, Los Angeles, California (Y.Z.); and CIC bioGUNE, Ciberehd, Bizkaia, Spain (J.M.M.).
authors.forename: Parizad
authors.initials: P
authors.lastname: Panthaki
authors.affiliation: Division of Gastroenterology, Cedars Sinai Medical Center, Los Angeles, California (T.W.H.L., H.P., H.Y., S.C.L.); University of Southern California Research Center for Liver Diseases, Keck School of Medicine, Los Angeles, California (T.W.H.L., H.P., H.Y., S.K., P.P., S.C.L.); Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital Los Angeles, Los Angeles, California (Y.Z.); and CIC bioGUNE, Ciberehd, Bizkaia, Spain (J.M.M.).
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Division of Gastroenterology, Cedars Sinai Medical Center, Los Angeles, California (T.W.H.L., H.P., H.Y., S.C.L.); University of Southern California Research Center for Liver Diseases, Keck School of Medicine, Los Angeles, California (T.W.H.L., H.P., H.Y., S.K., P.P., S.C.L.); Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital Los Angeles, Los Angeles, California (Y.Z.); and CIC bioGUNE, Ciberehd, Bizkaia, Spain (J.M.M.).
authors.forename: José M
authors.initials: JM
authors.lastname: Mato
authors.affiliation: Division of Gastroenterology, Cedars Sinai Medical Center, Los Angeles, California (T.W.H.L., H.P., H.Y., S.C.L.); University of Southern California Research Center for Liver Diseases, Keck School of Medicine, Los Angeles, California (T.W.H.L., H.P., H.Y., S.K., P.P., S.C.L.); Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital Los Angeles, Los Angeles, California (Y.Z.); and CIC bioGUNE, Ciberehd, Bizkaia, Spain (J.M.M.) Shelly.lu@cshs.org.
authors.forename: Shelly C
authors.initials: SC
authors.lastname: Lu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003839:Deoxyadenosines / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D012436:S-Adenosylmethionine / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013872:Thionucleosides / Q000494:pharmacology*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D003839:Deoxyadenosines; D013872:Thionucleosides; D051176:beta Catenin; C008500:5'-methylthioadenosine; D012436:S-Adenosylmethionine