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

Genistein is an isoflavenoid found in soy that has antitumorigenic activities. Treatment of colorectal carcinoma HCT-116 cells with 50 muM genistein results in a 50% reduction in cell proliferation and a 6-fold increase in apoptosis. Genistein induces nonsteroidal anti-inflammatory drug-activated gene I (NAG-I), a protein with antiturnorigenic 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-I expression is mediated by p53. In contrast, NAG-I is not induced by genistein in the p53-negative colorectal carcinoma cell line HCT-15. Luciferase reporter constructs of the NAG-I promoter containing 2 p53 sites showed that the p53 sites within the NAG-1 promoter are critical to genistein-induced NAG4 expression in p53-positive U20S cells. The expression of p53 was critical for NAG4 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 NAG4 forming a novel pathway responsible for the antiturnorigenic activity of genistein. (C) 2003 Wiley-Liss, Inc.