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.
Footnotes
- Received August 29, 2014.
- Accepted October 22, 2014.
This work was supported by the National Institutes of Health National Center for Complementary and Alternative Medicine [Grants R01-AT001576 and R01-AT004896 to S.C.L. and J.M.M.]; Plan Nacional of I+D SAF 2011-29851; and Departamento de Educación del Gobierno Vasco (J.M.M.). HepG2, Huh7, RKO, HCT116, and SW480 cells were provided by the Cell Separation and Culture Core, and confocal microscopy was done at the Imaging Core of the University of Southern California Research Center for Liver Diseases supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant P30-DK48522].
↵This article has supplemental material available at molpharm.aspetjournals.org.
- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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