3,3′-diindolylmethane, a major acid condensation product of indole-3-carbinol, induce expression of NAG-1 and ATF3 in colorectal cancer cells.

Proc Amer Assoc Cancer Res, Volume 47, 2006 5589 Epidemiological studies have suggested that nutrition plays an important role in carcinogenesis and dietary factors have been estimated to account for up to 80% of cancers of the gastrointestinal tract and approximately 30% of cancer morbidity and mortality might be prevented with proper adjustment of diets. 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. The present study was performed to investigate whether I3C and DIM influence the expression of the TGF-β superfamily gene NAG-1 (nonsteroidal anti-inflammatory drug-activated gene-1) and ATF3 (activating transcription factor 3), that are associated with pro-apoptotic and anti-tumorigenic activities. I3C repressed cell proliferation and induced NAG-1 expression in a concentration-dependent manner. DIM increased the expression of NAG-1 as well as the promoter activity of NAG-1 in a p53 independent manner. The induction of ATF3 was earlier than that of NAG-1 and up-regulated NAG-1 expression, suggesting a possible mechanism of ATF3-mediated NAG-1 expression. The DIM treatment increased the levels of ATF3 mRNA and protein via transcriptional regulation through a PKC-dependent pathway. Our results suggest that I3C repress cell proliferation through up-regulation of NAG-1, and ATF3 may play a pivotal role in DIM-induced NAG-1 expression in human colorectal cancer cells.