Targeting to the non-genomic activity of retinoic acid receptor-gamma by acacetin in hepatocellular carcinoma

We recently demonstrated that retinoic acid receptor-gamma(RAR gamma) is overexpressed and acts as a tumor promoter in hepatocellular carcinoma (HCC). The oncogenic activity of RAR gamma is mainly attributed to its physiological interaction with p85 alpha regulatory subunit of PI3K leading to constitutive activation of AKT. Here we report RAR gamma. as a negative regulator of p53 signaling and thus extend the oncogenic potential of RAR gamma to a new role in controlling the balance between AKT and p53. A natural flavonoid acacetin is then identified to be capable of modulating RAR gamma-dependent AKT-p53 network. It specifically binds to RAR gamma and inhibits all-trans retinoic acid (atRA) stimulation of RAR gamma transactivation. However, the anticancer action of acacetin is independent on its modulation of RAR gamma-driven transcriptional activity. Acacetin induces cancer cell apoptosis through antagonizing the non-genomic effect of RAR gamma on AKT and p53. When bound to RAR gamma, acacetin prevents RAR gamma from its activation of AKT followed by recovery of the normal p53 signaling. Given the implication of AKT-p53 dysregulation in most HCC, targeting the non-genomic signaling of RAR gamma. that switches AKT-p53 from a pro-survival to a pro-apoptotic program in cancer cells should be a promising strategy for developing novel anti-HCC drugs.