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Glabridin arrests cell cycle and inhibits proliferation of hepatocellular carcinoma by suppressing braf/MEK signaling pathway

  • Original Article
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Tumor Biology

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.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (31170676, 81372137), the Scientific Research Foundation for the Returned Overseas Chinese Scholars, the State Education Ministry (2014-1685), and the Scientific Research Foundation for Returned Overseas Scholars of Guangdong Medical University, China (B2012082). This work was also supported by the funds from the 2013 Sail Plan “the Introduction of the Shortage of Top-Notch Talent” Project (YueRenCaiBan [2014] 1), Science and Technology Planning Project (2013B021800072), and Education Discipline Construction Project (2013KJCX0090) of Guangdong Province, China. Finally, we thank Dr Feng Zhu from Huazhong University of Scientific and Technology for putting forward useful suggestions in the experiment as well as Schrödinger for providing an evaluation license.

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Authors and Affiliations

  1. China-America Cancer Research Institute, Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Dongguan Scientific Research Center, Guangdong Medical University, Dongguan, 523808, China

    Ziyou Wang, Shengqun Luo, Zheng Wan, Chuyan Chen, Xiangning Zhang, Binbin Li, GuoLiang Huang, Liyong Chen, Zhiwei He & Zunnan Huang

  2. Department of Pathophysiology, Guangdong Medical University, No. 1 Xincheng Road, Dongguan, 523808, China

    Ziyou Wang, Shengqun Luo, Xiangning Zhang, Binbin Li, Zhiwei He & Zunnan Huang

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  1. Ziyou Wang
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  2. Shengqun Luo
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Correspondence to Zhiwei He or Zunnan Huang.

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Wang, Z., Luo, S., Wan, Z. et al. Glabridin arrests cell cycle and inhibits proliferation of hepatocellular carcinoma by suppressing braf/MEK signaling pathway. Tumor Biol. 37, 5837–5846 (2016). https://doi.org/10.1007/s13277-015-4177-5

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  • DOI: https://doi.org/10.1007/s13277-015-4177-5

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