Targeting Non-Genomic Activity of Retinoic Acid Receptor-Gamma by Acacetin

Retinoic acid receptors (RARs) are ligand-dependent transcription factors of nuclear hormone receptor superfamily (NR). They are important pharmacological targets and current drug development paradigms are largely based on their nuclear transcription mechanism (genomic action). However, the side effects and limited therapeutic efficacy of retinoid-like drugs with such strategy remain a problem in clinical practice. Increasing evidences have demonstrated that many NRs including RARs can act outside the nucleus in a transcription-independent manner (non-genomic action), which are often implicated in human pathological conditions, suggesting that targeting to the non-genomic signaling of NRs is an alternative method for drug discovery. We recently reported that acacetin could antagonize the non-genomic action of RARγ via tipping the balance of AKT-p53 driven by RARγ from tumor promoting to tumor suppressive effect. This chapter provides methodology for identification of acacetin as a ligand and regulator of non-genomic signaling of RARγ. These laboratory protocols should be helpful for those researchers and beginners who are passionate about identifying chemical leads to probe the non-genomic roles of RARs and other NRs for developing new therapeutic technologies.