Targeting to the non-genomic activity of retinoic acid receptor-gamma by acacetin in hepatocellular carcinoma.
Targeting to the non-genomic activity of retinoic acid receptor-gamma by acacetin in hepatocellular carcinoma.
复制标题
金合欢素靶向肝细胞癌中视黄酸受体-γ的非基因组活性
DOI：
10.1038/s41598-017-00233-5
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发表时间：
2017-03-23
影响因子：
4.6
通讯作者：
Zeng JZ
中科院分区：
文献类型：
--
作者：
Zeng W;Zhang C;Cheng H;Wu YL;Liu J;Chen Z;Huang JG;Ericksen RE;Chen L;Zhang H;Wong AS;Zhang XK;Han W;Zeng JZ
我们最近证明，视黄酸受体-γ (RARγ)在肝细胞癌（HCC）中过度表达并作为肿瘤启动子。RARγ的致癌活性主要归因于其与PI3K的p85α调控亚基的生理相互作用，导致AKT的组成性激活。在这里，我们报道了RARγ作为p53信号的负调节因子，从而将RARγ的致癌潜力扩展到控制AKT和p53之间平衡的新作用。一种天然的类黄酮乙酰素随后被鉴定为能够调节rar γ依赖性AKT-p53网络。它特异性结合RARγ并抑制全反式维甲酸（atRA）刺激RARγ的反式活化。然而，acacetin的抗癌作用独立于其对rar γ驱动的转录活性的调节。Acacetin通过拮抗RARγ对AKT和p53的非基因组效应诱导癌细胞凋亡。当与RARγ结合时，acacetin阻止RARγ激活AKT，随后恢复正常的p53信号传导。考虑到大多数HCC中AKT-p53的失调，靶向RARγ的非基因组信号，将AKT-p53从促生存程序转换为促凋亡程序，应该是开发新型抗HCC药物的一个有希望的策略。
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.