NR4A orphan receptors and cancer

Abstract

NR4A orphan receptors are members of the nuclear receptor (NR) superfamily of transcription factors and include NR4A1 (Nur77,TR3, NGFI-B), NR4A2 (Nurr1), and NR4A3 (Nor1). NR4A receptors are immediate-early genes induced by multiple stimuli and modulate gene expression by interacting as monomers or homodimers to NGFI-B response elements (NBREs) and Nur-responsive elements (NuREs), respectively. NR4A1 and NR4A2 (but not NR4A3) also form heterodimers with the retinoic acid X receptor (RXR) that bind a DR5 motif, and there is evidence that NR4A1 can activate or deactivate gene expression in cancer cells through interactions with DNA-bound specificity protein 1(Sp1) transcription factor. NR4A receptors play important roles in cellular homeostasis and disease, and there is increasing evidence that they exhibit pro-oncogenic activity in most tumors and thereby represent novel targets for chemotherapeutic drugs. Many apoptosis-inducing drugs induce nuclear export of NR4A1 and activate apoptosis in cancer cell lines through formation of extranuclear complexes including a pro-apoptotic mitochondrial NR4A1-bcl-2 complex. 1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methane analogs exhibit structure-dependent activation or deactivation of nuclear NR4A1 to induce apoptosis, whereas cytosporone B and structural analogs activate both nuclear and extranuclear NR4A1-dependent pro-apoptotic pathways.The roles of NR4A2 and NR4A3 in carcinogenesis are less well-defined; however, there is evidence suggesting that NR4A receptors are important targets for development of new mechanism-based anticancer drugs.