Abstract 856: Association of high levels of folate with increased risk for colitis-associated colorectal neoplasia

Abstract

Abstract Low folate levels are known to be a risk factor for multiple human diseases including colorectal cancer. However, the relationship between folate levels and the prevention or development of colorectal cancer remains controversial. Patients with ulcerative colitis often possess low levels of folate due to inadequate intake and malabsorption of nutrients. Thus, folic acid supplementation is highly recommended despite very limited information regarding the effect of folic acid on the progression of colitis-associated colorectal cancer. The major objectives of the present study are to evaluate folate levels during the progression of colitis-associated colon cancer and to assess the potential functional role of folic acid supplementation on the growth of colon cancer cells. To study the effect of inflammation on levels of folate, acute and chronic colitis were induced within the mouse colon by administering 2 cycles of 3% dextran sulfate sodium (DSS) following one injection of azoxymethane (AOM; 7.4 mg/kg); a regimen that ultimately leads to the formation of colitis-associated dysplasias and carcinomas. At 10+, 12 and 19 wks of age, corresponding to acute colitis, chronic colitis, and colitis-associated dysplasia, respectively, blood samples were collected retro-orbitally and plasma folate levels were measured using stable isotope dilution liquid chromatography-multiple reaction monitoring/mass spectrometry. At sacrifice, the histopathology of the colon was correlated with plasma folate levels. Levels of plasma folate were reduced 33% (78.4 + 7.2 nM vs. 116.2 + 15.6 nM, p<0.05) and 21% (110. 4 + 5.2 nM vs. 138.2 + 10.8 nM, p<0.05) in AOM/DSS-treated mice at 10+ or 12 wks of age, respectively, as compared to age-matched mice treated with AOM alone. Surprisingly, plasma folate levels were elevated 12% in AOM/DSS-treated mice exhibiting multiple colitis-associated dysplasias (19 wks of age), as compared to control mice without tumors treated with AOM only. Administration of 5-aminosalicylic acid (5-ASA) to colitic mice at 75 mg/kg, a dose that inhibits the multiplicity of dysplasias by 50%, decreased plasma folate to a level lower than that of AOM/DSS controls (77.9 +10.7 nM vs. 199.0 + 25.1 nM, p<0.001). The effect of folic acid supplementation on cellular signaling pathways was evaluated in SW480 colon carcinoma cells cultured in the presence of low- or high-dose folic acid. Western blot analyses using antibodies against phospho-ERK1/2 and phospho-GSK3β revealed that exposure to high-dose folic acid increased phosphorylated ERK1/2 and reduced phosphorylated GSK3β by 2.0- and 2.5-fold, respectively, as compared to cells exposed to low-dose folic acid. These in vitro and in vivo data, when combined, suggest that high levels of folic acid may increase risk for colitis-associated neoplasia via the ERK/MAPK and GSK3β pathways. Supported by NIH R01 CA124693. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 856. doi:10.1158/1538-7445.AM2011-856