ONTD induces growth arrest and apoptosis of human hepatoma Bel-7402 cells though a peroxisome proliferator-activated receptor gamma-dependent pathway
ONTD induces growth arrest and apoptosis of human hepatoma Bel-7402 cells though a peroxisome proliferator-activated receptor gamma-dependent pathway
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ONTD 通过过氧化物酶体增殖物激活受体 γ 依赖性途径诱导人肝癌 Bel-7402 细胞生长停滞和凋亡
DOI：
10.1016/j.tiv.2017.08.012
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发表时间：
2017
影响因子：
3.2
通讯作者：
Ji Hui
中科院分区：
文献类型：
--
作者：
Tan Jiani;Shen Weixing;Shi Wenjing;Chen Xi;Sun Dongdong;Xu Changliang;Yan Qiuying;Cheng Haibo;Lai Yisheng;Ji Hui
ONTD（3-Oxo-29-noroleana-1，9（11），12-trien-2，20-dicarbonitrile）是大黄酸（GA）的一种新型衍生物，具有抗炎和抗肿瘤活性，但其作用机制尚不清楚。以前，我们证明了ONTD通过MAPK依赖的线粒体途径诱导人肝癌细胞凋亡。最近发现，ONTD增加亚G1积累和Annexin-V阳性染色，表明凋亡诱导作用。实验还发现，ONTD可提高肝癌细胞Bel-7402的PPAR-γ活性，降低Akt磷酸化水平，增加磷酸酶和张力蛋白同源物（phosphatase and tensin homologue，PTEN）蛋白表达，并与抑制细胞增殖有关。更重要的是，这些作用可以被特异性的PPAR-γ拮抗剂GW 9662所减弱，这表明ONTD可以作为PPAR-γ的配体。综上所述，我们的新观察结果表明，ONTD可能在HCC预防和治疗中具有潜在的意义，并首次表明，ONTD的抗肿瘤作用也可能通过调节PPAR-γ活化和PTEN/Akt信号通路介导。本研究也支持ONT作为一种潜在的候选药物用于HCC的化学预防或化学治疗。
ONTD (3-Oxo-29-noroleana-1,9(11),12-trien-2,20-dicarbonitrile) is a novel synthetic derivative of glycyrrhetinic acid (GA), which has been reported to exhibit anti-inflammatory and anti-tumor activities through its mechanisms are not fully understood. Previously, we demonstrated that ONTD induces apoptosis of human hepatoma cells via a MAPK-dependent mitochondrial pathway. Recently, ONTD was found to increase sub-G1 accumulation and Annexin-V positive staining, indicating apoptotic induction effect. It was also be found that ONTD increase the PPAR-γ activity, reduce the phosphorylation of Akt and increase phosphatase and tensin homologue (PTEN) protein expression in hepatocellular carcinoma (HCC) Bel-7402 cells, and these were associated with the inhibition of cells proliferation. More importantly, these effects could be diminished by GW9662, a specific PPAR-γ antagonist, suggesting that ONTD can act as a ligand of PPAR-γ. Taken together, our novel observations suggested that ONTD may have potential implication in HCC prevention and treatment, and showed for the first time that the anti-tumor effect of ONTD may also be mediated through modulation of the PPAR-γ activation and mediated by the PTEN/Akt signaling pathway. The present study also supports ONTD as a potential drug candidate for chemoprevention or chemotherapy of HCC.