TQ inhibits hepatocellular carcinoma growth in vitro and in vivo via repression of Notch signaling.

Xiquan Ke,Shuixiang He,Zhipeng Xu,Yulan Cheng,Dan Zhang,Xinlan Lu,Guifang Lu,Zhe Wang,Yan Zhao,Yuanyuan Liu,Stephen J Meltzer,Zhenguo Sun,Mudan Ren,Jee Hoon Song

doi:10.18632/oncotarget.5362

Abstract

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.

Highlights

Hepatocellular carcinoma (HCC) is the sixth most frequently diagnosed cancer and the third most common cause of cancer death worldwide
To explore whether Notch1 is expressed in HCC cells, Quantitative real-time PCR (qRT-PCR) analysis was performed in seven HCC cell lines and in primary normal liver epithelial cells (L-02)
TQ extracted from Nigella sativa has been used by multiple human societies for centuries, and this substance has shown anti-tumor activity against lymphoblastic leukemia, breast cancer, prostate, and pancreatic cancer cells [10,11,12,13]

Summary

Introduction

Hepatocellular carcinoma (HCC) is the sixth most frequently diagnosed cancer and the third most common cause of cancer death worldwide. An estimated 748,300 new cases and 695,900 cancer deaths occurred from HCC in 2008. Half of these cases and deaths were estimated to occur in China [1]. HCC incidence rates are increasing rapidly in many parts of the world, including the United States and Europe [2,3]. Curative treatments for early-stage HCC include surgical resection, liver transplantation, and ablation. Palliative therapy for intermediate-advanced HCC includes transarterial chemoembolization (TACE) and sorafenib [5,6,7], but curative effect is difficult to achieve. Effective treatment agents are urgently needed in this disease

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