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1 Veterans Affairs Medical Center, Wayne State University School of Medicine, Detroit, MI, USA
2 Veterans Affairs Medical Center, Wayne State University School of Medicine, Detroit, MI, USA; Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA; Department of Internal Medicine, Wayne State University School of Medicine, Detroit, MI, USA
3 Veterans Affairs Medical Center, Wayne State University School of Medicine, Detroit, MI, USA; Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA
4 Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA; Department of Internal Medicine, Wayne State University School of Medicine, Detroit, MI, USA
* To whom correspondence should be addressed. E-mail: a.majumdar{at}wayne.edu.
Although accumulating evidence suggests a chemopreventive role for folic acid in colorectal carcinogenesis, the underlying mechanisms are largely unknown. Previously, we reported that supplemental folic acid inhibits the expression and activation of EGF-receptor (EGFR) in colon cancer cell lines. To determine the mechanism(s) by which folate affects EGFR function, we have examined whether and to what extent supplemental folic acid or its metabolites 5-methyltetrahydrofolate (MTF), dihydrofolate (DF) or tetrahydrofolate (TF) will modulate the basal and serum-induced activation of the EGFR promoter in HCT-116 colon cancer cell line. HCT-116 cells were preincubated with or without (control) folic acid or one of its metabolites (10 µg/ml) for 48 h, subsequently transfected with EGFR promoter luciferase reporter construct followed by a 48 h incubation with folic acid, DF, TF or 5-MTF in the absence or presence of 10% FBS. Supplemental folic acid as well as its metabolites markedly inhibited EGFR promoter activity and its methylation status. Exposure of the cells to 10% FBS caused a marked stimulation of EGFR promoter activity and its expression, both of which were greatly abrogated by supplemental folic acid and 5-MTF. In contrast, the serum-induced activation of c-fos promoter activity was unaffected by 5-MTF. The 5-MTF-induced inhibition of the serum-mediated stimulation of EGFR promoter activity and EGFR expression was reversed when methylation was inhibited by 5-aza-2'deoxycytidine. Our data suggest that folate and its metabolite 5-MTF inhibit EGFR promoter activity in colon cancer cells by enhancing methylation. This could partly be responsible for folic acid mediated inhibition of growth related processes in colorectal neoplasia.
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