The Anticancer Mechanism Of Acacetin Targeting RAR_γ And Regulating AKT-p53Signal Pathway

The nuclear retinoic acid receptors (RAR; α, β, and y), a key member of nuclear receptor superfamily, play essential roles in regulation of cell growth, proliferation, immune, differentiation, metabolism, apoptosis, autophagy, homeostasis, etc, and are excellent pharmacological targets in human solid and hematological malignancies. We and others have recently reported that RARy is overexpressed in several tumors and acts as an oncogenic protein through activation of the PI3K/AKT survival pathway.In this study, we further investigated the regulation of RARy-mediated PI3K/AKT signaling in cancer cells and found that acacetin (5,7-dihydroxy-4’-methoxyflavone), an active flavonoid compound from traditional Chinese medicine Flos Chrysanthemi Indici, could act as a potent modulator of the pathway. We showed that acacetin specifically bound to RARy with an IC50of12.5μM, and it induced cancer cell apoptosis in a RARy-dependent manner as HepG2liver cancer cells as well as MCF-7breast cancer cells with the high RARy expression were sensitivity to the apoptotic effect of acacetin while SW480colon cancer cells with the tow RARy expression were not Interestingly, acacetin bound to RARy in a transcriptionally antagonistic orientation and the binding resulted in inactivation of AKT. We further demonstrated that acacetin inactivation of AKT was closely associated with increased p53expression and activation of Bax, providing a molecular basis for the apoptotic effect of acacetin. Together, our findings demonstrated that acacetin could target p53-AKT network for inducing apoptosis of cancer cells through its binding to RARy. Since flavonoids represent potential promising drug leads enriched in food and medicinal plants, identification of the target and action mode of acacetin provide a new basis for deve toping improved flavo noid-based drugs.