Ke Xiquan, Zhao Yan, Lu Xinlan, Wang Zhe, Liu Yuanyuan, Ren Mudan, Lu Guifang, Zhang Dan, Sun Zhenguo, Xu Zhipeng, Song Jee Hoon, Cheng Yulan, Meltzer Stephen J, He Shuixiang
Department of Gastroenterology, the First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Department of Gastroenterology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China.
Oncotarget. 2015 Oct 20;6(32):32610-21. doi: 10.18632/oncotarget.5362.
Thymoquinone (TQ) has been reported to possess anti-tumor activity in various types of cancer. However, its effects and molecular mechanism of action in hepatocellular carcinoma (HCC) are still not completely understood. We observed that TQ inhibited tumor cell growth in vitro, where treatment with TQ arrested the cell cycle in G1 by upregulating p21 and downregulating cyclinD1 and CDK2 expression; moreover, TQ induced apoptosis by decreasing expression of Bcl-2 and increasing expression of Bax. Simultaneously, TQ demonstrated a suppressive impact on the Notch pathway, where overexpression of NICD1 reversed the inhibitory effect of TQ on cell proliferation, thereby attenuating the repressive effects of TQ on the Notch pathway, cyclinD1, CDK2 and Bcl-2, and also diminishing upregulation of p21 and Bax. In a xenograft model, TQ inhibited HCC growth in nude mice; this inhibitory effect in vivo, as well as of HCC cell growth in vitro, was associated with a discernible decline in NICD1 and Bcl-2 levels and a dramatic rise in p21 expression. In conclusion, TQ inhibits HCC cell growth by inducing cell cycle arrest and apoptosis, achieving these effects by repression of the Notch signaling pathway, suggesting that TQ represents a potential preventive or therapeutic agent in HCC patients.
据报道，百里醌（TQ）在多种癌症类型中具有抗肿瘤活性。然而，其在肝细胞癌（HCC）中的作用及其分子作用机制仍未完全明确。我们观察到，TQ在体外抑制肿瘤细胞生长，TQ处理通过上调p21并下调细胞周期蛋白D1（cyclinD1）和细胞周期蛋白依赖性激酶2（CDK2）的表达使细胞周期停滞于G1期；此外，TQ通过降低Bcl-2的表达并增加Bax的表达诱导细胞凋亡。同时，TQ对Notch信号通路具有抑制作用，NICD1的过表达逆转了TQ对细胞增殖的抑制作用，从而减弱了TQ对Notch信号通路、cyclinD1、CDK2和Bcl-2的抑制作用，也减少了p21和Bax的上调。在异种移植模型中，TQ抑制裸鼠体内的HCC生长；这种体内抑制作用以及体外对HCC细胞生长的抑制作用与NICD1和Bcl-2水平的明显下降以及p21表达的显著升高有关。总之，TQ通过诱导细胞周期停滞和细胞凋亡抑制HCC细胞生长，通过抑制Notch信号通路实现这些作用，提示TQ是HCC患者潜在的预防或治疗药物。
