PT  - JOURNAL ARTICLE
AU  - Tony W.H. Li
AU  - Hui Peng
AU  - Heping Yang
AU  - Steven Kurniawidjaja
AU  - Parizad Panthaki
AU  - Yuhua Zheng
AU  - Jose M. Mato
AU  - Shelly C. Lu
TI  - S-adenosylmethionine and Methylthioadenosine Inhibit Beta Catenin Signaling by Multiple Mechanisms in Liver and Colon Cancer
AID  - 10.1124/mol.114.095679
DP  - 2014 Jan 01
TA  - Molecular Pharmacology
PG  - mol.114.095679
4099  - http://molpharm.aspetjournals.org/content/early/2014/10/22/mol.114.095679.short
4100  - http://molpharm.aspetjournals.org/content/early/2014/10/22/mol.114.095679.full
AB  - 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 beta catenin expression on immunohistochemistry in a murine colitis-associated colon cancer (CAC) model. Here we examined the molecular mechanisms involved. SAMe or MTA treatment in the CAC model lowered total beta 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 beta catenin levels by 68%. In both cases, lower cyclin D1 and c-Myc expression correlated with lower beta catenin levels. In liver (HepG2) and colon (SW480, HCT116) cancer cells with constitutively active beta catenin signaling, SAMe and MTA treatment inhibited beta catenin activity by excluding it from the nuclear compartment. However, in liver (Huh-7) and colon (RKO) cancer cells expressing wild type Wnt/beta catenin, SAMe and MTA accelerated beta catenin degradation by a GSK-β-dependent mechanism. Both agents lowered AKT activity but this was not mediated by inhibiting phosphoinositide 3-kinase. Instead, both agents increased the activity of protein phosphatase 2A, which inactivates AKT. The effect of MTA on lowering beta 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/beta 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.