Indole-3-carbinol and 3,3'-diindolylmethane induce expression of NAG-1 in a p53-independent manner.
Indole-3-carbinol (I3C), present in cruciferous vegetables, and its major in vivo product 3,3'-diindolylmethane (DIM), have been reported to suppress cancer development. However, the responsible molecular mechanisms are not fully understood. Nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) is a TGF-beta superfamily gene associated with pro-apoptotic and anti-tumorigenic activities. The present study was performed to investigate whether I3C and DIM influence NAG-1 expression and to provide the potential molecular mechanism of their effects on anti-tumorigenesis. The I3C repressed cell proliferation and induced NAG-1 expression in a concentration-dependent manner. In addition, DIM increased the expression of NAG-1 as well as activating transcription factor 3 (ATF3), and the induction of ATF3 was earlier than that of NAG-1. The DIM treatment increased luciferase activity of NAG-1 in HCT-116 cells transfected with NAG-1 promoter construct. The results suggest that I3C represses cell proliferation through up-regulation of NAG-1 and that ATF3 may play a pivotal role in DIM-induced NAG-1 expression in human colorectal cancer cells. Furthermore, the mixture of I3C with resveratrol enhances NAG-1 expression, suggesting the synergistic effect of these two unrelated compounds on NAG-1 expression.
Lee
Seong-Ho
SH
Laboratory of Environmental Carcinogenesis, Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996, USA.
Kim
Jong-Sik
JS
Yamaguchi
Kiyoshi
K
Eling
Thomas E
TE
Baek
Seung Joon
SJ
D051700:Activating Transcription Factor 3; D000970:Antineoplastic Agents / Q000008:administration & dosage; D049109:Cell Proliferation / Q000187:drug effects*; D016207:Cytokines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055436:Growth Differentiation Factor 15; D045325:HCT116 Cells; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D000077185:Resveratrol; D013267:Stilbenes / Q000008:administration & dosage*; D015534:Trans-Activators / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism*
C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D000970:Antineoplastic Agents; D016207:Cytokines; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D007211:Indoles; D013267:Stilbenes; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; C016517:indole-3-carbinol; D000077185:Resveratrol; C016392:3,3'-diindolylmethane