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 anti-tumorigenic activities. Treatment of colorectal carcinoma HCT-116 cells with 50 microM 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.
Wilson
Leigh C
LC
Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Baek
Seung Joon
SJ
Call
Allison
A
Eling
Thomas E
TE
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology*; D055436:Growth Differentiation Factor 15; D006801:Humans; D007700:Kinetics; D009154:Mutation; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation
D000970:Antineoplastic Agents; D016207:Cytokines; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D016159:Tumor Suppressor Protein p53; D019833:Genistein