Diindolylmethane analogs bind NR4A1 and are NR4A1 antagonists in colon cancer cells. Academic Article uri icon


  • 1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methane (C-DIM) compounds exhibit antineoplastic activity in multiple cancer cell lines and the p-hydroxyphenyl analog (DIM-C-pPhOH) inactivates nuclear receptor 4A1 (NR4A1) in lung and pancreatic cancer cell lines. Using a series of 14 different p-substituted phenyl C-DIMs, we show that several compounds including DIM-C-pPhOH directly interacted with the ligand binding domain of NR4A1. Computational-based molecular modeling studies showed high-affinity interactions of DIM-C-pPhOH and related compounds within the ligand binding pocket of NR4A1, and these same compounds decreased NR4A1-dependent transactivation in colon cancer cells transfected with a construct containing 3 tandem Nur77 binding response elements linked to a luciferase reporter gene. Moreover, we also show that knockdown of NR4A1 by RNA interference (small interfering NR4A1) or treatment with DIM-C-pPhOH and related compounds decreased colon cancer cell growth, induced apoptosis, decreased expression of survivin and other Sp-regulated genes, and inhibited mammalian target of rapamycin signaling. Thus, C-DIMs such as DIM-C-pPhOH directly bind NR4A1 and are NR4A1 antagonists in colon cancer cells, and their antineoplastic activity is due, in part, to their interactions with nuclear NR4A1.

published proceedings

  • Mol Endocrinol

altmetric score

  • 1

author list (cited authors)

  • Lee, S., Li, X. i., Hedrick, E., Jin, U., Tjalkens, R. B., Backos, D. S., ... Safe, S.

citation count

  • 67

complete list of authors

  • Lee, Syng-Ook||Li, Xi||Hedrick, Erik||Jin, Un-Ho||Tjalkens, Ronald B||Backos, Donald S||Li, Li||Zhang, Yi||Wu, Qiao||Safe, Stephen

publication date

  • October 2014