Orphan nuclear receptor 4A1 (NR4A1) and novel ligands

Abstract

The nuclear receptor (NR) superfamily of transcription factors encodes expression of 48 human genes that are important for maintaining cellular homeostasis and in pathophysiology, and this has been observed for all sub-families including orphan receptors for which endogenous ligands have not yet been identified. The orphan NR4A1 (Nur77 and TR3) and other members of this sub-family (NR4A2 and NR4A3) are immediate early genes induced by diverse stressors, and these receptors play an important role in the immune function and are up-regulated in some inflammatory diseases including solid tumors. Although endogenous ligands for NR4A have not been identified, several different classes of compounds have been characterized as NR4A1 ligands that bind the receptor. These compounds include cytosporone B and structurally related analogs, bis-indole derived (CDIM) compounds, the triterpenoid celastrol and a number of other chemicals including polyunsaturated fatty acids. NR4A1 ligands bind different regions/surfaces of NR4A1 and exhibit selective NR4A1 modulator (SNR4AM) activities that are dependent on ligand structure and cell/tissue context. NR4A1 ligands exhibit pharmacologic activities in studies on cancer, endometriosis metabolic and inflammatory diseases and are promising agents with clinical potential for treating multiple diseases.

Keywords: Agonists; Antagonists; Ligands; NR4A1.

Figure 1.

A. Structures of CsnB and related compounds and celastrol B. Mechanisms associated with PDNPA inducing dissociation of NR4A1 from p38 (51) and (B) effects of celastrol and oxidized DIM compounds inducing nuclear export of NR4A1 which forms a pro-apoptotic NR4A1-bcl2 complex that target mitochondria (54).

Figure 2.

Multiple pro-oncogenic pathways/gene regulated by NR4A1 in solid tumors that are inhibited by CDIM/NR4A1 antagonists. Results of NR4A1 knockdown and subsequent functional and genomic analysis have identified several pathways and genes responsible for cancer cell proliferation, survival, migration and invasion (rev. in 20). These pathways have been primarily determined in receptor knockdown studies and similar responses are observed after treatment with CDIM/NR4A1 antagonists.

Figure 3.

Structures of CDIM8 and buttressed analogs substituted at X and Y, and oxidized CDIMs (20, 68, 69). CDIM8 contains a 4-hydroxyl group on the phenyl ring and has been used extensively as a prototypical NR4A1 ligand and the 3,5-substituted buttressed analogs of CDIM8 are more potent as NR4A1 antagonists in both cell culture and in vivo studies (68, 72). The 4-carboxymethyl analogs was also active as an NR4A1 ligand. The oxidized CDIMs are prepared from the corresponding CDIMs and induced NR4A1-dependent anticancer activity and induce nuclear export or NR4A1 (73, 74).

Figure 4.

Transactivation mechanisms associated with CDIM/NR4A1 ligands including activation of NR4A1 monomer (A), homodimer (B) and NR4A1/Sp (C) and NR4A1/RXR heterodimer (D); It has also been demonstrated that TGFβ-induced invasion induces nuclear export of NR4A1 in breast cancer cells (48) which can be blocked by CDIMs (E) and CDIMs also activate cytosolic NR4A1 in RD rhabdomyosarcoma cells to bind bcl2 (F) to form a pro-apoptotic complex which interacts with bcl-2 (83).