title: Glabridin arrests cell cycle and inhibits proliferation of hepatocellular carcinoma by suppressing braf/MEK signaling pathway.
abstract: Glabridin, an isoflavone isolated from licorice, owns a variety of pharmacological effects. Several reports have demonstrated that glabridin could regulate multiple cellular signaling pathways to inhibit the progression of cancer. However, the target proteins have not been elucidated yet. We used shape screening and induced fit docking to screen the protein data bank against glabridin. Braf and MEK1/2, important intermediate molecules of the braf/MEK cascade, were identified as the potential targets of glabridin. The experimental data showed that glabridin could inhibit the phosphorylation of MEK1/2 and the phosphorylation levels of downstream molecules including ERK1/2 and transcription factors ATF1 and CREB, but had no effect on the phosphorylation of braf. In particular, the in vitro pull-down assay indicated that glabridin selectively bound to braf and MEK1/2. What is more, exposure to glabridin significantly suppressed the proliferation of hepatocellular carcinoma HepG2 cell line. In addition, glabridin might arrest cell cycle in G1 through downregulation of cyclinD3, CDK2, and CDK4. In conclusion, glabridin is a potential multi-molecule-targeting inhibitor in the field of clinical prevention or treatment of cancer.
authors.affiliation: China-America Cancer Research Institute, Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Dongguan Scientific Research Center, Guangdong Medical University, Dongguan, 523808, China.|Department of Pathophysiology, Guangdong Medical University, No. 1 Xincheng Road, Dongguan, 523808, China.
authors.forename: Ziyou
authors.initials: Z
authors.lastname: Wang
authors.affiliation: China-America Cancer Research Institute, Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Dongguan Scientific Research Center, Guangdong Medical University, Dongguan, 523808, China.|Department of Pathophysiology, Guangdong Medical University, No. 1 Xincheng Road, Dongguan, 523808, China.
authors.forename: Shengqun
authors.initials: S
authors.lastname: Luo
authors.affiliation: China-America Cancer Research Institute, Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Dongguan Scientific Research Center, Guangdong Medical University, Dongguan, 523808, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wan
authors.affiliation: China-America Cancer Research Institute, Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Dongguan Scientific Research Center, Guangdong Medical University, Dongguan, 523808, China.
authors.forename: Chuyan
authors.initials: C
authors.lastname: Chen
authors.affiliation: China-America Cancer Research Institute, Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Dongguan Scientific Research Center, Guangdong Medical University, Dongguan, 523808, China.|Department of Pathophysiology, Guangdong Medical University, No. 1 Xincheng Road, Dongguan, 523808, China.
authors.forename: Xiangning
authors.initials: X
authors.lastname: Zhang
authors.affiliation: China-America Cancer Research Institute, Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Dongguan Scientific Research Center, Guangdong Medical University, Dongguan, 523808, China.|Department of Pathophysiology, Guangdong Medical University, No. 1 Xincheng Road, Dongguan, 523808, China.
authors.forename: Binbin
authors.initials: B
authors.lastname: Li
authors.affiliation: China-America Cancer Research Institute, Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Dongguan Scientific Research Center, Guangdong Medical University, Dongguan, 523808, China.
authors.forename: GuoLiang
authors.initials: G
authors.lastname: Huang
authors.affiliation: China-America Cancer Research Institute, Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Dongguan Scientific Research Center, Guangdong Medical University, Dongguan, 523808, China.
authors.forename: Liyong
authors.initials: L
authors.lastname: Chen
authors.affiliation: China-America Cancer Research Institute, Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Dongguan Scientific Research Center, Guangdong Medical University, Dongguan, 523808, China. zhiweihe688@yahoo.com.|Department of Pathophysiology, Guangdong Medical University, No. 1 Xincheng Road, Dongguan, 523808, China. zhiweihe688@yahoo.com.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: He
authors.affiliation: China-America Cancer Research Institute, Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Dongguan Scientific Research Center, Guangdong Medical University, Dongguan, 523808, China. zn_huang@yahoo.com.|Department of Pathophysiology, Guangdong Medical University, No. 1 Xincheng Road, Dongguan, 523808, China. zn_huang@yahoo.com.
authors.forename: Zunnan
authors.initials: Z
authors.lastname: Huang
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D019295:Computational Biology; D015195:Drug Design; D056945:Hep G2 Cells; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000473:pathology*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008958:Models, Molecular; D010636:Phenols / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000502:physiology; D014410:Tumor Stem Cell Assay
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D007529:Isoflavones; D010636:Phenols; D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; C107601:glabridin
keywords: Braf; Computational modeling; Drug design; Glabridin; HepG2; MEK1/2