Indole-3-carbinol and 3,3'-diindolylmethane induce expression of NAG-1 in a p53-independent manner

Biochem Biophys Res Commun. 2005 Mar 4;328(1):63-9. doi: 10.1016/j.bbrc.2004.12.138.


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.

MeSH terms

  • Activating Transcription Factor 3
  • Antineoplastic Agents / administration & dosage
  • Cell Proliferation / drug effects*
  • Cytokines / metabolism*
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation, Neoplastic / drug effects
  • Growth Differentiation Factor 15
  • HCT116 Cells
  • Humans
  • Indoles / administration & dosage*
  • Resveratrol
  • Stilbenes / administration & dosage*
  • Trans-Activators / metabolism*
  • Tumor Suppressor Protein p53 / deficiency
  • Tumor Suppressor Protein p53 / metabolism*


  • ATF3 protein, human
  • Activating Transcription Factor 3
  • Antineoplastic Agents
  • Cytokines
  • GDF15 protein, human
  • Growth Differentiation Factor 15
  • Indoles
  • Stilbenes
  • Trans-Activators
  • Tumor Suppressor Protein p53
  • indole-3-carbinol
  • Resveratrol
  • 3,3'-diindolylmethane