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

Abstract

We recently demonstrated that retinoic acid receptor-γ (RARγ) is overexpressed and acts as a tumor promoter in hepatocellular carcinoma (HCC). The oncogenic activity of RARγ is mainly attributed to its physiological interaction with p85α regulatory subunit of PI3K leading to constitutive activation of AKT. Here we report RARγ as a negative regulator of p53 signaling and thus extend the oncogenic potential of RARγ to a new role in controlling the balance between AKT and p53. A natural flavonoid acacetin is then identified to be capable of modulating RARγ-dependent AKT-p53 network. It specifically binds to RARγ and inhibits all-trans retinoic acid (atRA) stimulation of RARγ transactivation. However, the anticancer action of acacetin is independent on its modulation of RARγ-driven transcriptional activity. Acacetin induces cancer cell apoptosis through antagonizing the non-genomic effect of RARγ on AKT and p53. When bound to RARγ, acacetin prevents RARγ 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 RARγ 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.

Role of Dietary Antioxidants in p53‐Mediated Cancer Chemoprevention and Tumor Suppression

“…Further, kaempferol warrants as an antiangiogenetic agent, which reduced human umbilical vein endothelial cell viability-induced DNA damage and DNA fragmentation through activating the levels of caspase-3, caspase-8, and caspase-9 signaling, which were upregulated by ROS-mediated p53/ATM molecules following stimulations of p53 downstream protein levels of Fas/CD95, death receptor 4 (DR4), and DR5 [ 166 ]. Another study revealed acacetin, an O-methylated flavone, which can strongly inhibit tumor growth and induce tumor shrinkage in mice, which is closely correlated with its increasing p53 expression accompanied by decreased retinoic acid receptor gamma (RAR γ ) and reduced AKT activity in liver cancer cell lines [ 167 ]. It was further reported that securin and p53 play an important role in determining the sensitivity of human colon cancer cells to fisetin.…”

Reversal of Multidrug Resistance in Cancer by Multi-Functional Flavonoids

“…Acacetin , O-methylated Apigenin, found in Robinia pseudoacacia, Turnera diffusa , and Betula pendula (87), exhibits anti-cancer effects in prostate cancer cells (88) and hepatocellular carcinoma (89) etc. Acacetin inhibits the activities and functions of both ABCB1 (90, 91) and ABCG2 (92).…”

Acacetin‐induced cell apoptosis in head and neck squamous cell carcinoma cells: Evidence for the role of muscarinic M3 receptor

“…Acacetin is identified to specifically bind to retinoic acid receptor‐γ (RARγ). Acacetin induces cancer cell apoptosis through antagonizing RARγ and modulating RARγ‐dependent AKT‐p53 network (Zeng et al, ). Our investigation confirmed that acacetin promoted mitochondrial cytochrome c release and caspase 9, 3 processing in HNSCC cells.…”