β-Thujaplicin induces autophagic cell death, apoptosis, and cell cycle arrest through ROS-mediated Akt and p38/ERK MAPK signaling in human hepatocellular carcinoma
β-Thujaplicin induces autophagic cell death, apoptosis, and cell cycle arrest through ROS-mediated Akt and p38/ERK MAPK signaling in human hepatocellular carcinoma
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β-Thujaplicin 通过 ROS 介导的 Akt 和 p38/ERK MAPK 信号传导在人肝细胞癌中诱导自噬性细胞死亡、凋亡和细胞周期停滞
DOI：
10.1038/s41419-019-1492-6
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发表时间：
2019-03-15
影响因子：
9
通讯作者：
Chen, Fengling
中科院分区：
文献类型：
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作者：
Zhang, Guangya;He, Jiangping;Chen, Fengling
肝细胞癌（HCC）是世界范围内常见的肝脏恶性肿瘤，具有很高的发病率和死亡率。β - thujaplicin是一种tropolone衍生物，已用于一些保健产品和临床辅助药物，但其用于HCC的用途尚不清楚。在这项研究中，我们发现β - thujaplicin抑制HCC细胞的生长，但不抑制正常肝细胞的生长，具有纳摩尔效力。在机制上，我们发现β - thujaplicin可以诱导自噬，通过western blot，共聚焦显微镜和透射电子显微镜判断。进一步使用β - thujaplicin联合自噬阻滞剂或激动剂治疗HepG2细胞，我们发现β - thujaplicin诱导ROS介导的自噬细胞死亡（ACD）引起Akt-mTOR信号通路的抑制。此外，β - thujaplicin可触发HepG2细胞凋亡，并增加cleaved PARP1、cleaved caspase-3和Bax/Bcl-2比值，表明β - thujaplicin通过线粒体依赖途径介导细胞凋亡。我们还发现p21的表达增加和参与β - thujaplicin的CDK7、Cyclin D1和Cyclin A2的表达减少导致s期阻滞。β - thujaplicin似乎是通过ros介导的p38/ERK MAPK发挥这些功能，而不是通过JNK信号通路激活。与体外研究结果一致，我们的体内研究证实β - thujaplicin治疗显著降低HepG2肿瘤异种移植物生长。综上所述，这些发现表明β - thujaplicin具有抗hcc细胞的能力，并可能促进新型抗癌药物的开发。
Hepatocellular carcinoma (HCC), a common liver malignancy worldwide, has high morbidity and mortality. beta-Thujaplicin, a tropolone derivative, has been used in some health-care products and clinical adjuvant drugs, but its use for HCC is unknown. In this study, we found that beta-Thujaplicin inhibits the growth of HCC cells, but not normal liver cells, with nanomolar potency. Mechanistically, we found that beta-Thujaplicin could induce autophagy, as judged by western blot, confocal microscopy, and transmission electron microscopy. Further using beta-Thujaplicin combined with an autophagy blocker or agonist treatment HepG2 cells, we found that beta-Thujaplicin induced autophagic cell death (ACD) mediated by ROS caused inhibition of the Akt-mTOR signaling pathway. Moreover, beta-Thujaplicin triggered HepG2 apoptosis and increased cleaved PARP1, cleaved caspase-3, and Bax/Bcl-2 ratio, which indicated that beta-Thujaplicin induced apoptosis mediated by the mitochondrial-dependent pathway. We also found that increased expression of p21 and decreased expression of CDK7, Cyclin D1, and Cyclin A2 participating in beta-Thujaplicin caused the S-phase arrest. It seems that beta-Thujaplicin exerts these functions by ROS-mediated p38/ERK MAPK but not by JNK signaling pathway activation. Consistent with in vitro findings, our in vivo study verified that beta-Thujaplicin treatment significantly reduced HepG2 tumor xenograft growth. Taken together these findings suggest that beta-Thujaplicin have an ability of anti-HCC cells and may conducively promote the development of novel anti-cancer agents.