TQ inhibits hepatocellular carcinoma growth<i>in vitro</i>and<i>in vivo</i>via repression of Notch signaling

Abstract

// Xiquan Ke 1 , Yan Zhao 1 , Xinlan Lu 1 , Zhe Wang 2 , Yuanyuan Liu 3 , Mudan Ren 1 , Guifang Lu 1 , Dan Zhang 1 , Zhenguo Sun 4 , Zhipeng Xu 5 , Jee Hoon Song 6 , Yulan Cheng 6 , Stephen J. Meltzer 6 , Shuixiang He 1 1 Department of Gastroenterology, the First Affiliated Hospital, School of Medicine, Xi&rsquo;an Jiaotong University, Xi&rsquo;an, Shaanxi 710061, P.R. China 2 Department of Gastroenterology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China 3 Department of Gastroenterology, Xi&rsquo;an Central Hospital, Xi&rsquo;an, Shaanxi 710000, P.R. China 4 Department of Thoracic Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China 5 Department of Gastroenterology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China 6 Division of Gastroenterology, Departments of Medicine and Oncology and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA Correspondence to: Shuixiang He, e-mail: hesx123@gmail.com Stephen J. Meltzer, e-mail: smeltzer@jhmi.edu Keywords: thymoquinone, hepatocellular carcinoma, Notch, cell cycle, apoptosis Received: May 29, 2015&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: September 10, 2015&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: September 21, 2015 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.