A chemoprotective fish oil/pectin diet regulates the expression of the bcl-2 oncogene by altering CpG island methylator phenotype (CIMP) in colon cancer
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We have demonstrated that diets containing fish oil and pectin (FO/P) reduce colon tumor incidence relative to those containing corn oil and cellulose (CO/C) in part by inducing apoptosis. CO/C, as compared to FO/P, promotes colonocyte expression of the antiapoptotic protein, bcl2, and bcl2 promoter methylation is altered in colon cancer. To determine if CO/C promotes bcl2 expression by reducing promoter methylation in colon cancer, we examined bcl2 promoter methylation and mRNA levels, and colonocyte apoptosis (TUNEL assay). Rats were provided diets containing FO/P or CO/C, and were terminated 36 wk after azoxymethane injection (2, 15 mg/kg BW, sc). DNA isolated from 10 m sections of PFAfixed colon carcinomas was bisulfite modified and amplified by real time qPCR to assess regions of the bcl2 CpG islands. Scraped mucosa from the same rats was also used to quantify bcl2 mRNA levels. FO/P treatment increased bcl2 DNA methylation (p = 0.055) and apoptosis (p = 0.022) as compared to CO/C. Data analysis revealed a negative relationship between bcl2 DNA methylation and bcl2 mRNA levels. We conclude that dietary FO/P promotes apoptosis by enhancing bcl2 promoter methylation relative to a CO/C diet. This study is the first to detect a diet effect on promoter methylation of the bcl2 oncogene in the colon. Funded by NSBRI NASA NCC 958 and NIH CA59034.
