Wogonin inhibits cell cycle progression by activating the glycogen synthase kinase-3 beta in hepatocellular carcinoma

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Ming Hong1, Mohammed M Almutairi2, Siying Li2

  • 1Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China; Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China.

Phytomedicine : International Journal of Phytotherapy and Phytopharmacology
|January 29, 2020
PubMed
Abstract

Insights

Wogonin inhibits hepatocellular carcinoma (HCC) progression by targeting Cyclin D1. This natural compound promotes Cyclin D1 degradation through GSK3beta activation, leading to cell cycle arrest and suppressed tumor growth.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Wogonin exhibits known anti-inflammatory, anti-microbial, and anti-tumor properties.
  • Wogonin has been shown to down-regulate Cyclin D1 activity in various cancer types.
  • The precise mechanisms underlying wogonin's anti-cancer effects, particularly its impact on Cyclin D1, require further elucidation.

Purpose of the Study:

  • To investigate the potential of wogonin in suppressing hepatocellular carcinoma (HCC) progression.
  • To elucidate the mechanism by which wogonin inhibits Cyclin D1 expression in HCC.

Main Methods:

  • In vitro anti-tumor activity assessed via MTT and clonogenic assays.
  • Cell cycle progression analyzed using flow cytometry.
  • Mechanism explored through Western blot, immunofluorescence, co-immunoprecipitation, molecular docking, SPR, site-directed mutagenesis, and immunohistochemistry.
  • In vivo efficacy evaluated using orthotopic xenograft mouse models.

Main Results:

  • Wogonin (10-20 µM) inhibited proliferation and cell cycle progression in HCC cell lines (MHCC97L, HepG2).
  • Wogonin promoted Cyclin D1 ubiquitination and degradation, linked to phosphorylation at Thr286.
  • Wogonin activated GSK3beta, enhancing Cyclin D1 phosphorylation and proteolysis.
  • In vivo studies confirmed decreased Cyclin D1 and increased phospho-GSK3beta in HCC specimens post-wogonin treatment.

Conclusions:

  • Wogonin suppresses HCC proliferation and induces cell cycle arrest.
  • A novel mechanism involves wogonin-induced GSK3beta activation, leading to Cyclin D1 degradation.
  • Wogonin presents a potential therapeutic agent for hepatocellular carcinoma.
Keywords:
Cell cycle progressionHepatocarcinomaPhosphorylationWogonin

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