Targeting NR4A1 (TR3) in cancer cells and tumors

Expert Opin Ther Targets. 2011 Feb;15(2):195-206. doi: 10.1517/14728222.2011.547481. Epub 2011 Jan 5.


Introduction: Nuclear receptor 4A1(NR4A1) (testicular receptor 3 (TR3), nuclear hormone receptor (Nur)77) is a member of the nuclear receptor superfamily of transcription factors and is highly expressed in multiple tumor types. RNA interference studies indicate that NR4A1 exhibits growth-promoting, angiogenic and prosurvival activity in most cancers.

Areas covered: Studies on several apoptosis-inducing agents that activate nuclear export of NR4A1, which subsequently forms a mitochondrial NR4A1-bcl-2 complex that induces the intrinsic pathway for apoptosis are discussed. Cytosporone B and related compounds that induce NR4A1-dependent apoptosis in cancer cells through both modulation of nuclear NR4A1 and nuclear export are discussed. A relatively new class of diindolylmethane analogs (C-DIMs) including 1,1-bis(3'-indolyl)-1-(p-methoxyphenyl)methane (DIM-C-pPhOCH(3)) (NR4A1 activator) and 1,1-bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) (NR4A1 deactivator) are discussed in more detail. These anticancer drugs (C-DIMs) act strictly through nuclear NR4A1 and induce apoptosis in cancer cells and tumors.

Expert opinion: It is clear that NR4A1 plays an important pro-oncogenic role in cancer cells and tumors, and there is increasing evidence that this receptor can be targeted by anticancer drugs that induce cell death via NR4A1-dependent and -independent pathways. Since many of these compounds exhibit relatively low toxicity, they represent an important class of mechanism-based anticancer drugs with excellent potential for clinical applications.

Publication types

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

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Humans
  • Indoles / pharmacology
  • Mice
  • Molecular Targeted Therapy*
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / antagonists & inhibitors
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / genetics
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism*
  • Phenols / pharmacology
  • Phenylacetates / metabolism
  • Phenylacetates / pharmacology*
  • RNA Interference


  • 1,1-bis(3'-indolyl)-1-(4-hydroxyphenyl)methane
  • Antineoplastic Agents
  • Indoles
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Phenols
  • Phenylacetates
  • cytosporone B