Targeting NR4A1 (TR3) in cancer cells and tumors

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-pPhOCH₃) (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.