The Critical Role Of RARγ In Cross-talk Between PI3K/AKT And NF-κB Signal Pathways

Retinoids,a group of natural or synthetic vitamin A derivatives,play an important role in the regulation of cell proliferation,differentiation and apoptosis. Some of these compounds have been developed as effective anticancer drugs.The biological actions of retinoids are primarily mediated through two classes of nuclear receptors,retinoic acid receptors(RARs) and retinoid X receptors(RXRs). Both RAR and RXR are encoded by three distinct genes,α,β,andγ,which are highly conserved amongst species and spatiotemporally expressed in developing embryos and adult tissues.Their distinct distributions suggest that individual isotypes may have unique and specific function.In this study,we show that the expression level of RARγvaries among different tissues and that it is frequently overexpressed in liver tumors.Using in vitro cell culture system,we find that RARγupon binding to its ligand all-trans-retinoic acid (ATRA) interacts with the p85αregulatory subunit of the phosphoinositide 3-kinase (PI3K),leading to activation of PI3K and its downstream target AKT.The activation of PI3K/AKT signaling is accompanied with phosphorylation and degradation of inhibitor ofκBα(IκBα),which then stimulates nuclear translocation of p65/RelA and and NF-κB transcriptional activity.Based on our mechanistic studies,we have also screened a natural products library for antagonizing the RARγ-mediated NF-κB pathway and successfully identified a flavonoid derivative Acacetin that can induce RARγdegradation and inhibition of RARγ-mediated activation of PI3K/AKT/NF-κB signaling.Together,our results demonstrate that RARγfunctions to induce inflammation of liver cancer cells and their growth by nongenomically activating the PI3K/AKT/NF-κB pathway,suggesting that it may represents an attractive molecular target for developing anti-liver cancer agents.Our results also suggest that Acacetin is a promising lead for developing new agents for treating liver cancer.