Methionine adenosyltransferase (MAT) is an essential enzyme that catalyzes the formation of S- adenosylmethionine (SAMe). In mammals, the catalytic subunit of MAT is encoded by two genes, MAT1A and MAT2A, while a third gene MAT2?, encodes for a regulatory subunit ? that regulates MAT2A-encoded enzyme. MAT1A is expressed in liver while MAT2A is widely distributed. In hepatocytes, increased MAT2A and MAT2? expression increased growth. SAMe inhibits hepatocyte growth, is pro-apoptotic in liver cancer cells but anti- apoptotic in normal hepatocytes. Regulation of MAT genes and whether MAT and SAMe regulate growth and death in colon cancer cells are unknown. We found increased MAT2A and MAT2? mRNA levels in resected colon cancer specimens as compared to adjacent normal tissue. This occurred due to increased transcription. MAT2A mRNA levels are also increased in the polyps of Min mice. EGF, IGF-1 and leptin, three mitogens implicated in the pathogenesis and invasiveness of colon cancer, induced MAT2A expression and growth in colon cancer cell lines RKO and HT29. Lowering MAT2A expression by RNAi reduced growth and blocked the mitogenic effects of these growth factors. SAMe and its metabolite methylthioadenosine (MTA) lowered MAT2A expression and prevented the ability of growth factors to induce MAT2A and cell proliferation. Furthermore, SAMe and MTA inhibited growth of colon cancer cells by inducing apoptosis. A novel target identified is cFLIP, which is down-regulated by both SAMe and MTA. Finally, overexpression increased, while reduced expression of MAT2? inhibited growth and caused apoptosis. The current proposal will extend these novel observations in five specific aims: 1. Examine transcriptional regulation of MAT2A in colon cancer cell lines ? we will determine how MAT2A is transcriptionally regulated at baseline and in response to growth factors, SAMe and MTA;2. elucidate the molecular mechanism(s) of MAT2A and MAT2? up-regulation in colon cancer ? we will use resected colon cancer and normal tissue specimens to elucidate the mechanisms of their up-regulation;3. determine how MAT genes influence growth and death of colon cancer cells ? we will determine how MAT2A and MAT2? regulate growth and apoptosis;4. elucidate the mechanisms of SAMe and MTA-induced apoptosis in colon cancer cells ? we will define the molecular mechanisms and examine whether normal colon epithelial cells are affected;and 5. Assess changes in MAT expression during tumor formation and efficacy of SAMe and MTA in chemoprevention and treatment of intestinal tumors ? we will examine whether SAMe and MTA can prevent spontaneous polyp formation in Min mice, and halt progression and reverse already established aberrant crypt foci in Min mice treated with azoxymethane. Successful completion of these studies should greatly enhance our understanding of the role of MAT and SAMe in colon cancer pathogenesis and may provide a novel therapeutic approach for both chemoprevention and treatment of colon polyps and cancer, topics that are highly relevant to public health. PROJECT NARRATIVE Colon cancer remains one of the most common cancers in the western world. At the present time effective chemopreventive therapy that is devoid of side effects is lacking. The goals of this project are to investigate a new paradigm in colon cancer development and see if S-adenosylmethionine (SAMe), a nutritional supplement widely available, and its metabolite methylthioadenosine (MTA) can be effective in the chemoprevention and treatment of colon cancer.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Research Project (R01)
Project #
5R01AT004896-05
Application #
8248755
Study Section
Special Emphasis Panel (ZRG1-DIG-C (04))
Program Officer
Hopp, Craig
Project Start
2008-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2012
Total Cost
$382,448
Indirect Cost
$131,897
Name
University of Southern California
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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Tomasi, Maria Lauda; Ryoo, Minjung; Ramani, Komal et al. (2015) Methionine adenosyltransferase ?2 sumoylation positively regulate Bcl-2 expression in human colon and liver cancer cells. Oncotarget 6:37706-23
Rodríguez-Suárez, Eva; Gonzalez, Esperanza; Hughes, Chris et al. (2014) Quantitative proteomic analysis of hepatocyte-secreted extracellular vesicles reveals candidate markers for liver toxicity. J Proteomics 103:227-40
Tomasi, Maria Lauda; Ryoo, Minjung; Yang, Heping et al. (2014) Molecular mechanisms of lipopolysaccharide-mediated inhibition of glutathione synthesis in mice. Free Radic Biol Med 68:148-58
Huidobro, Covadonga; Toraño, Estela G; Fernández, Agustín F et al. (2013) A DNA methylation signature associated with the epigenetic repression of glycine N-methyltransferase in human hepatocellular carcinoma. J Mol Med (Berl) 91:939-50
Mato, José M; Martínez-Chantar, M Luz; Lu, Shelly C (2013) S-adenosylmethionine metabolism and liver disease. Ann Hepatol 12:183-9
Tomás-Loba, Antonia; Bernardes de Jesus, Bruno; Mato, Jose M et al. (2013) A metabolic signature predicts biological age in mice. Aging Cell 12:93-101
Martínez-Uña, Maite; Varela-Rey, Marta; Cano, Ainara et al. (2013) Excess S-adenosylmethionine reroutes phosphatidylethanolamine towards phosphatidylcholine and triglyceride synthesis. Hepatology 58:1296-305
Tomasi, Maria Lauda; Ryoo, Minjung; Skay, Anna et al. (2013) Polyamine and methionine adenosyltransferase 2A crosstalk in human colon and liver cancer. Exp Cell Res 319:1902-11
Peng, Hui; Dara, Lily; Li, Tony W H et al. (2013) MAT2B-GIT1 interplay activates MEK1/ERK 1 and 2 to induce growth in human liver and colon cancer. Hepatology 57:2299-313

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