The Expression, Regulation And Significance Of RXRα In Liver Cancer And Identification Of Natural Leads That Induce RXRα To Export Resulting In Extensive Apoptosis

Nuclear hormone receptors (NHRs) represent one of the most important drug targets. Retinoid X receptor-alpha (RXRα), a member of the nuclear receptor superfamily, plays critical role in the regulation of diverse biological process. It has been shown that RXRαplays a critical role in the development of the liver cancer. In this study, we investigated the mechanism by which RXRαmediates the apoptotic effect of chemotherapeutic agents in liver cancer cells. In addition, we screened a natural herb library for new leads targeting at RXRαthrough different strategies, including biochemical and cell-based assays. Our results showed that 12-0-tetradecanoylphorbol-13-acetate (TPA) and COX-2 inhibitor diclofenac significantly induced apoptosis in liver cancer cells by different mechanisms. Diclofenac induced extensive RXRa protein modification, probably through phosphorylation in liver cancer cells, which was associated with growth inhibition and apoptosis. TPA promoted apoptosis via degradation of RXRαprotein and inhibition of RXRαtranscriptional activity. In addition, we observed that TPA significantly up-regulated expression levels of TR3 mRNA in SMMC7721 liver cancer cells, suggesting that increased TR3 mRNA played a role by heterodimerizing with RXRα. We also found that an herb extract named RZC...