Regulation of the nongenomic actions of retinoid X receptor-α by targeting the coregulator-binding sites

Abstract

Retinoid X receptor-α (RXRα), a unique member of the nuclear receptor superfamily, represents an intriguing and unusual target for pharmacologic interventions and therapeutic applications in cancer, metabolic disorders and neurodegenerative diseases. Despite the fact that the RXR-based drug Targretin (bexarotene) is currently used for treating human cutaneous T-cell lymphoma and the fact that RXRα ligands (rexinoids) show beneficial effects in the treatment of cancer and diseases, the therapeutic potential of RXRα remains unexplored. In addition to its conventional transcription regulation activity in the nucleus, RXRα can act in the cytoplasm to modulate important biological processes, such as mitochondria-dependent apoptosis, inflammation, and phosphatidylinositol 3-kinase (PI3K)/ AKT-mediated cell survival. Recently, new small-molecule-binding sites on the surface of RXRα have been identified, which mediate the regulation of the nongenomic actions of RXRα by a class of small molecules derived from the nonsteroidal anti-inflammatory drug (NSAID) Sulindac. This review discusses the emerging roles of the nongenomic actions of RXRα in the RXRα signaling network, and their possible implications in cancer, metabolic and neurodegenerative disorders, as well as our current understanding of RXRα regulation by targeting alternate binding sites on its surface.

Sulindac‐derived retinoid X receptor‐α modulator attenuates atherosclerotic plaque progression and destabilization in ApoE−/− mice

“…Although RXRα has been recognized as an intriguing drug target for many years, the side effects associated with regulating its transcriptional activity have hampered the development of RXRα‐based drugs (Zhang et al, ). Here, we reported that the sulindac‐derived RXRα modulator K‐80003 significantly mitigated the progression and destabilization of carotid atherosclerotic plaques in ApoE −/− mice without any apparent toxicity to animals.…”

“…Retinoid X receptor-α (RXRα) is a unique member of the nuclear receptor superfamily (Zhang et al, 2015), involved in the regulation of several cellular processes including inflammation (Desreumaux et al, 2001;Nunez et al, 2010). Numerous studies have reported the effects of RXRα ligands (rexinoids) on atherogenesis (Claudel et al, 2001;Lalloyer et al, 2006;Staels, 2001;Streb & Miano, 2003).…”

Endocrine-disrupting chemicals and fatty liver disease

“…Perhaps the most prominent of these are the steroid hormone receptors — oestrogen receptors (ERα and ERβ), androgen receptor (AR) and progesterone receptor (PR) 43, 44 . In addition to these steroid receptors, accumulating evidence suggests that other NRs (for example, peroxisome proliferator-activated receptor γ (PPARγ) 45 , retinoid X receptor α (RXRα) 46 , truncated thyroid receptor α (TRα) isoforms 44, 47 and retinoic acid receptors (RARα and RARγ 48 )) might also signal via a similar mechanism. Non-genomic signalling does have the potential to affect the genome and alter transcription, as kinases activated in non-genomic signaling pathways can phosphorylate and regulate the activity of epigenomic programmers, transcription factors and/or their associated coregulators, even in the absence of a liganded NR interacting with target genes.…”

Family reunion of nuclear hormone receptors: structures, diseases, and drug discovery

“…In addition to their functions in transcription control, nuclear receptors are also involved in nongenomic actions of cell response to hormones and they are also targeted by regulation of signaling from cell surface receptors. Zhang and coworkers provide a detail review of regulation of nongenomic actions of retinoid X receptor-α by targeting the coregulator-binding sites [10] . Li and coworkers review the signaling cascade from cell surface receptors to nuclear receptors in the pathways of bile acid metabolism [11] .…”