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Esculetin Inhibits Cancer Cell Glycolysis by Binding Tumor PGK2, GPD2, and GPI

Song-Tao Wu1, Bo Liu1,2,3, Zhong-Zhu Ai1,2,3

  • 1Faculty of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China.

Frontiers in Pharmacology
|April 16, 2020
PubMed

Insights

Esculetin inhibits tumor cell glycolysis by targeting key enzymes like phosphoglycerate kinase 2 (PGK2), glycerol-3-phosphate dehydrogenase (GPD2), and glucose-6-phosphate isomerase (GPI). This compound shows potential as an anticancer agent by disrupting cancer cell energy metabolism.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Glycolysis supports tumor cell survival and proliferation, especially under hypoxic conditions.
  • Targeting glycolysis offers a strategy for malignant tumor treatment.
  • Key glycolysis enzymes include phosphoglycerate kinase 2 (PGK2), glycerol-3-phosphate dehydrogenase (GPD2), and glucose-6-phosphate isomerase (GPI).

Purpose of the Study:

  • To identify potential therapeutic targets within glycolysis pathways.
  • To investigate the anti-cancer effects of esculetin on tumor cell metabolism.
  • To explore the interactions between glycolysis-related proteins.

Main Methods:

  • Combined transcriptome, proteomics, and reverse docking to screen target proteins.
  • Utilized microscale thermophoresis (MST) to determine binding constants.
  • Assessed cellular lactate production and glucose consumption in HepG2 cells.
  • Performed animal tests to evaluate anti-cancer effects.

Main Results:

  • Esculetin demonstrated strong binding to PGK2, GPD2, and GPI.
  • Esculetin significantly inhibited glycolysis in HepG2 cells.
  • Direct interaction was observed between GPD2 and GPI.
  • Animal studies indicated esculetin's anti-cancer effects via PGK2, GPD2, and GPI modulation.

Conclusions:

  • Esculetin affects glucose metabolism by binding to glycolytic proteins, exhibiting anti-tumor activity.
  • PGK2, GPD2, and GPI are potential novel therapeutic targets for esculetin-mediated cancer treatment.
  • The direct interaction between GPD2 and GPI highlights a novel regulatory mechanism in glycolysis.
Keywords:
GPD2/GPIesculetinglycolysismicroscale thermophoresisprotein inhibitorproteomicstranscriptome

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