Nonsteroidal anti‐inflammatory drug‐activated gene (NAG‐1) is induced by genistein through the expression of p53 in colorectal cancer cells

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Abstract
Genistein is an isoflavenoid found in soy that has anti‐tumorigenic activities. Treatment of colorectal carcinoma HCT‐116 cells with 50 μM genistein results in a 50% reduction in cell proliferation and a 6‐fold increase in apoptosis. Genistein induces nonsteroidal anti‐inflammatory drug‐activated gene 1 (NAG‐1), a protein with antitumorigenic activities, in a time‐ and concentration‐dependent manner in HCT‐116 cells. In addition, p53 and p21 are induced in HCT‐116 cells. The induction of p53 (3 hr) precedes the induction of NAG‐1 (12 hr), suggesting that genistein‐induced NAG‐1 expression is mediated by p53. In contrast, NAG‐1 is not induced by genistein in the p53‐negative colorectal carcinoma cell line HCT‐15. Luciferase reporter constructs of the NAG‐1 promoter containing 2 p53 sites showed that the p53 sites within the NAG‐1 promoter are critical to genistein‐induced NAG‐1 expression in p53‐positive U2OS cells. The expression of p53 was critical for NAG‐1 promoter activity since no promoter activity was observed with genistein treatment in HCT‐15 cells. However, genistein‐induced promoter activity was restored in HCT‐15 cells by transfection with wild‐type p53. Together our data suggest a relationship between genistein, p53 and NAG‐1 forming a novel pathway responsible for the antitumorigenic activity of genistein.

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