Targeting truncated RXRα for cancer therapy

Abstract

Retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a well-established drug target, representing one of the most important targets for pharmacologic interventions and therapeutic applications for cancer. However, how RXRα regulates cancer cell growth and how RXRα modulators suppress tumorigenesis are poorly understood. Altered expression and aberrant function of RXRα are implicated in the development of cancer. Previously, several studies had demonstrated the presence of N-terminally truncated RXRα (tRXRα) proteins resulted from limited proteolysis of RXRα in tumor cells. Recently, we discovered that overexpression of tRXRα can promote tumor growth by interacting with tumor necrosis factor-alpha-induced phosphoinositide 3-kinase and NF-κB signal transduction pathways. We also identified nonsteroidal anti-inflammatory drug Sulindac and analogs as effective inhibitors of tRXRα activities via a unique binding mechanism. This review discusses the emerging roles of tRXRα and modulators in the regulation of cancer cell survival and death as well as inflammation and our recent understanding of tRXRα regulation by targeting the alternate binding sites on its surface.

Keywords: PI3K; RXRα modulators; inflammation; nongenomic action; tRXRα.

Figure 1.

The scheme of RXRα/tRXRα and its ligands (A) Schematic representation of RXRα and tRXRα. DBD, DNA-binding domain; LBD, ligand-binding domain; AF-1, activation function 1; AF-2, activation function 2. (B) Chemical structures of 9-cis-RA, Targretin, UAB30 and peretinoin.

Figure 2.

The nongenomic tRXRα actions The cytoplasmic tRXRα acts through its interaction with TNFα-signaling proteins to regulate cell survival, inflammation, and apoptosis. tRXRα effect is negatively regulated by its modulator Sulindac (S). In addition, tRXRα may target mitochondria through heterodimerization with Nur77 to modulate mitochondria-dependent apoptosis.

Figure 3.

Chemical structures of molecules that act via binding to novel binding regions in RXRα

Figure 4.

Novel binding regions in RXRα (A) K-8008 binds to a novel binding region: the K-8008 binding region is away from the 9-cis-RA binding area and located on the surface of monomeric RXRα. It shows the superposition of the monomer of RXRα-LBD/K-8008 complex structure (brown) and the apo protein structure (purple, from PDB entry 1G1U). K-8008 is shown as sticks (carbon in magenta and nitrogen in blue). The classic ligand-binding site is indicated by a VDW ball model of 9-cis-RA (in cyan/red) taken from a superimposed 1FBY of PDB. (B) The proposed binding region for compound 23. The compound 23-binding region overlaps with the coactivator-binding region. Here, compound 23 was docked to the structure 3FUG (in pink) of PDB and the docked conformation (in VDW balls) was displayed with the coactivator peptide (in green) in the structure of 3FUG.