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Liquiritin inhibits proliferation and induces apoptosis in HepG2 hepatocellular carcinoma cells via the ROS-mediated MAPK/AKT/NF-κB signaling pathway

Abstract

Liquiritin (LIQ), a major constituent of Glycyrrhiza Radix, exhibits various pharmacological activities. In this study, to explore the potential anti-cancer effects and its underlying molecular mechanisms of LIQ in hepatocellular carcinoma (HCC) cells. LIQ significantly decreased viability and induced apoptosis in HepG2 cells by decreasing mitochondrial membrane potential and regulating Bcl-2 family proteins, cytochrome c, cle-caspase-3, and cle-PARP. The cell cycle analysis and western blot analysis revealed that LIQ induced G2/M phase arrest through increased expression of p21 and decreased levels of p27, cyclin B, and CDK1/2. The flow cytometry and western blot analysis also suggested that LIQ promoted the accumulation of ROS in HepG2 cells and up-regulated the phosphorylation expression levels of p38 kinase, c-Jun N-terminal kinase (JNK), and inhibitor of NF-κB (IκB-α); the phosphorylation levels of extracellular signal-regulated kinase (ERK), protein kinase B (AKT), signal transducer activator of transcription 3 (STAT3), and nuclear factor kappa B (NF-κB) were down-regulated. However, these effects were reversed by N-acetyl-l-cysteine (NAC), MAPK, and AKT inhibitors. The findings demonstrated that LIQ induced cell cycle arrest and apoptosis via the ROS-mediated MAPK/AKT/NF-κB signaling pathway in HepG2 cells, and the LIQ may serve as a potential therapeutic agent for the treatment of human HCC.

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Funding

This work was funded by the Postdoctoral Scientific Research Foundation of Heilongjiang Province of China (No. LBH-Q13132), Heilongjiang Touyan Innovation Team Program (No.2019HTY078), “Regulation and activity retention technology and application of coarse cereals active components in processing” (No. 2017YFD0401203), and the Heilongjiang Farms & Land Reclamation Administration Support Project for Key Scientific Research (No. HKKYZD190705), The Heilongjiang Bayi Agricultural University Support program for ‘San Zong’(No.TDJH201905).

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Contributions

CHJ and LKC conceived and designed the study. JR W and TZL wrote the paper and performed some of the experiments. CW, YHL, and XJP assessed the cytotoxic effects. YCF, YZ, and WTX performed the apoptotic analyses. YZ and TZ performed the cell cycle analyses. SML, SNW, and HX performed the western blot analyses. HXW performed the signaling analyses. All of the authors have read and approved the final version of the manuscript.

Corresponding authors

Correspondence to Long-Kui Cao or Cheng-Hao Jin.

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The authors declare that they have no conflict of interest.

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Wang, JR., Li, TZ., Wang, C. et al. Liquiritin inhibits proliferation and induces apoptosis in HepG2 hepatocellular carcinoma cells via the ROS-mediated MAPK/AKT/NF-κB signaling pathway. Naunyn-Schmiedeberg's Arch Pharmacol 393, 1987–1999 (2020). https://doi.org/10.1007/s00210-019-01763-7

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  • DOI: https://doi.org/10.1007/s00210-019-01763-7

Keywords

  • Liquiritin
  • Human hepatocellular carcinoma cells
  • Apoptosis
  • Cell cycle arrest
  • Reactive oxygen species