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

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

Research output: Contribution to journalArticlepeer-review

79 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1729-1739
Number of pages11
JournalMolecular Endocrinology
Issue number10
StatePublished - Oct 1 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology


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