Diindolylmethane analogs bind NR4A1 and are NR4A1 antagonists in colon cancer cells

Mol Endocrinol. 2014 Oct;28(10):1729-39. doi: 10.1210/me.2014-1102. Epub 2014 Aug 6.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line, Tumor
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / metabolism
  • Humans
  • Indoles / pharmacology
  • Indoles / therapeutic use*
  • Models, Molecular
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / antagonists & inhibitors*
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism
  • Phenols / pharmacology
  • Phenols / therapeutic use*
  • RNA Interference


  • 1,1-bis(3'-indolyl)-1-(4-hydroxyphenyl)methane
  • Indoles
  • NR4A1 protein, human
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Phenols