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

ABSTRACT: We recently demonstrated that retinoic acid receptor-? (RAR?) is overexpressed and acts as a tumor promoter in hepatocellular carcinoma (HCC). The oncogenic activity of RAR? is mainly attributed to its physiological interaction with p85? regulatory subunit of PI3K leading to constitutive activation of AKT. Here we report RAR? as a negative regulator of p53 signaling and thus extend the oncogenic potential of RAR? 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?-dependent AKT-p53 network. It specifically binds to RAR? and inhibits all-trans retinoic acid (atRA) stimulation of RAR? transactivation. However, the anticancer action of acacetin is independent on its modulation of RAR?-driven transcriptional activity. Acacetin induces cancer cell apoptosis through antagonizing the non-genomic effect of RAR? on AKT and p53. When bound to RAR?, acacetin prevents RAR? 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? 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.

SUBMITTER: Zeng W 

PROVIDER: S-EPMC5428017 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature