title: Targeting NR4A1 (TR3) in cancer cells and tumors.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Bioscience and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Syng-Ook
authors.initials: SO
authors.lastname: Lee
authors.forename: Xi
authors.initials: X
authors.lastname: Li
authors.forename: Shaheen
authors.initials: S
authors.lastname: Khan
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010636:Phenols / Q000494:pharmacology; D010648:Phenylacetates / Q000378:metabolism / Q000494:pharmacology*; D034622:RNA Interference
chemical_list: C552530:1,1-bis(3'-indolyl)-1-(4-hydroxyphenyl)methane; D000970:Antineoplastic Agents; D007211:Indoles; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010636:Phenols; D010648:Phenylacetates; C531461:cytosporone B