Retinoid X receptor-alpha (RXRα) is a potent regulator of inflammatory responses; however, its therapeutic potential for inflammatory cancer remains to be explored. We previously discovered that RXRα is abnormally cleaved in tumor cells and tissues, producing a truncated RXRα (tRXRα). Here, we show that transgenic expression of tRXRα in mice accelerates the development of colitis-associated colon cancer (CAC). The tumorigenic effect of tRXRα is primarily dependent on its expression in myeloid cells, which results in interleukin-6 (IL-6) induction and STAT3 activation. Mechanistic studies reveal an extensive interaction between tRXRα and TRAF6 in the cytoplasm of macrophages, leading to TRAF6 ubiquitination and subsequent activation of the NF-κB inflammatory pathway. K-80003, a tRXRα modulator derived from nonsteroidal anti-inflammatory drug (NSAID) sulindac, suppresses the growth of tRXRα-mediated colorectal tumor by inhibiting the NF-κB-IL-6-STAT3 signaling cascade. These results provide new insight into tRXRα action and identify a promising tRXRα ligand for treating CAC.

Celastrol is one of the most studied natural products. Our studies show for the first time that celastrol can bind to its target protein via specific noncovalent interactions that position celastrol next to the thiol group of the reactive cysteine for reversible covalent bond formation. Such specific noncovalent interactions confer celastrol binding specificity and demonstrate the feasibility of improving the efficacy and selectivity of celastrol for therapeutic applications.

Nur77 (also called TR3 or NGFI-B), an orphan member of the nuclear receptor superfamily, induces apoptosis by translocating to mitochondria where it interacts with Bcl-2 to convert Bcl-2 from an antiapoptotic to a pro-apoptotic molecule. Nur77 posttranslational modification such as phosphorylation has been shown to induce Nur77 translocation from the nucleus to mitochondria. However, small molecules that can bind directly to Nur77 to trigger its mitochondrial localization and Bcl-2 interaction remain to be explored. Here, we report our identification and characterization of DIM-C-pPhCF₃⁺MeSO₃⁻ (BI1071), an oxidized product derived from indole-3-carbinol metabolite, as a modulator of the Nur77-Bcl-2 apoptotic pathway. BI1071 binds Nur77 with high affinity, promotes Nur77 mitochondrial targeting and interaction with Bcl-2, and effectively induces apoptosis of cancer cells in a Nur77- and Bcl-2–dependent manner. Studies with animal model showed that BI1071 potently inhibited the growth of tumor cells in animals through its induction of apoptosis. Our results identify BI1071 as a novel Nur77-binding modulator of the Nur77-Bcl-2 apoptotic pathway, which may serve as a promising lead for treating cancers with overexpression of Bcl-2.

Background and Purpose: Atherosclerosis is a chronic inflammatory disease, and retinoid X receptor‐α (RXRα) is an intriguing anti‐atherosclerosis target. This study investigated whether and how an RXRα modulator, K‐80003, derived from a non‐steroidal anti‐inflammatory drug attenuates atherosclerotic plaque progression and destabilization.Experimental Approach: Our previously established ApoE^−/− mouse model of carotid vulnerable plaque progression was treated with K‐80003 or vehicle for 4 or 8 weeks. Samples of carotid arteries and serum were collected to determine atherosclerotic lesion size, histological features, expression of related proteins, and lipid profiles. In vitro studies were carried out in 7‐ketocholesterol (7‐KC)‐stimulated macrophages treated with or without K‐80003.Key Results: K‐80003 significantly reduced lesion size, plaque rupture, macrophage infiltration, and inflammatory cytokine levels. Plaque macrophages positive for nuclear p65 (RelA) NF‐κB subunit were markedly reduced after K‐80003 treatment. Also, K‐80003 treatment inhibited 7‐KC‐induced p65 nuclear translocation, IκBα degradation, and transcription of NF‐κB target genes. In addition, K‐80003 inhibited NF‐κB pathway mainly through the reduction of p62/sequestosome 1 (SQSTM1), probably due to promotion of autophagic flux by K‐80003. Mechanistically, cytoplasmic localization of RXRα was associated with decreased autophagic flux. Increasing cytoplasmic RXRα expression by overexpression of RXRα/385 mutant decreased autophagic flux in RAW264.7 cells. Finally, K‐80003 strongly inhibited 7‐KC‐induced RXRα cytoplasmic translocation.Conclusions and Implications: K‐80003 suppressed atherosclerotic plaque progression and destabilization by promoting macrophage autophagic flux and consequently inhibited the p62/SQSTM1‐mediated NF‐κB proinflammatory pathway. Thus, targeting RXRα‐mediated autophagy‐inflammation axis by its noncanonical modulator may represent a promising strategy to treat atherosclerosis.

Modulation of the Nur77-Bcl-2 apoptotic pathway by p38 MAPK Modulation of the Nur77-Bcl-2 apoptotic pathway by p38α MAPK