Targeting NR4A1 (TR3) in cancer cells and tumors.

Abstract

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.

• Authors: Syng-Ook Lee, Xi Li, Shaheen Khan, Stephen Safe
• Journal: Expert opinion on therapeutic targets (Expert Opin Ther Targets) Vol. 15 Issue 2 Pg. 195-206 (Feb 2011) ISSN: 1744-7631 [Electronic] England
• PMID: 21204731 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Review)

Chemical References

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

Topics

• 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, metabolism, pathology)
• Nuclear Receptor Subfamily 4, Group A, Member 1 (antagonists & inhibitors, genetics, metabolism)
• Phenols (pharmacology)
• Phenylacetates (metabolism, pharmacology)
• RNA Interference