title: TQ inhibits hepatocellular carcinoma growth in vitro and in vivo via repression of Notch signaling.
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.
authors.affiliation: Department of Gastroenterology, the First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Xiquan
authors.initials: X
authors.lastname: Ke
authors.affiliation: Department of Gastroenterology, the First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Gastroenterology, the First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Xinlan
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Gastroenterology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Xi'an Central Hospital, Xi'an, Shaanxi 710000, P.R. China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, the First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Mudan
authors.initials: M
authors.lastname: Ren
authors.affiliation: Department of Gastroenterology, the First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Guifang
authors.initials: G
authors.lastname: Lu
authors.affiliation: Department of Gastroenterology, the First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Thoracic Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China.
authors.forename: Zhenguo
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Gastroenterology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Jee Hoon
authors.initials: JH
authors.lastname: Song
authors.affiliation: 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.
authors.forename: Yulan
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: 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.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Meltzer
authors.affiliation: Department of Gastroenterology, the First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Shuixiang
authors.initials: S
authors.lastname: He
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D016227:Benzoquinones / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051881:Receptor, Notch1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; D016227:Benzoquinones; D018797:Cell Cycle Proteins; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; C003466:thymoquinone
keywords: Notch; apoptosis; cell cycle; hepatocellular carcinoma; thymoquinone