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Ponicidin Promotes Hepatocellular Carcinoma Mitochondrial Apoptosis by Stabilizing Keap1-PGAM5 Complex

Bixin Zhao1, Zuhui Liang1, Lisheng Zhang2

  • 1State Key Laboratory of Traditional Chinese Medicine Syndrome, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|August 8, 2024
PubMed

Insights

Ponicidin, a diterpenoid, inhibits hepatocellular carcinoma (HCC) cell proliferation and migration by targeting the Keap1-PGAM5 complex. This mechanism activates mitochondrial apoptosis, offering a novel therapeutic strategy for HCC.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Hepatocellular carcinoma (HCC) is a significant global health challenge with limited effective treatments.
  • Ponicidin, a diterpenoid, has shown antitumor potential, but its mechanism against HCC is not fully understood.

Purpose of the Study:

  • To elucidate the mechanism of action of ponicidin in hepatocellular carcinoma (HCC).
  • To investigate ponicidin's effect on HCC cell proliferation, migration, and apoptosis.
  • To identify the molecular targets and pathways involved in ponicidin's anti-HCC activity.

Main Methods:

  • Target fishing using biotin-labeled ponicidin and HuProt™ Human Proteome Microarray V4.0.
  • Co-crystallization of PGAM5 peptide and Keap1 Kelch domain.
  • Molecular dynamics simulations to analyze protein-ligand interactions.
  • In vitro assays for cell proliferation, migration, and apoptosis.
  • In vivo xenograft tumor model in BALB/c nude mice.

Main Results:

  • Ponicidin significantly inhibited HCC cell proliferation and migration.
  • Ponicidin targets Keap1, promoting Keap1-PGAM5 complex formation and PGAM5 ubiquitination.
  • Ponicidin activates the mitochondrial apoptosis pathway via PGAM5, leading to ROS production and cell death.
  • Structural and simulation data confirmed ponicidin's role in stabilizing the Keap1-PGAM5 complex.
  • Ponicidin demonstrated significant tumor growth inhibition and apoptosis induction in vivo.

Conclusions:

  • Ponicidin exerts anti-HCC effects by targeting the Keap1-PGAM5 complex, inducing mitochondrial apoptosis.
  • This study reveals a novel mechanism for ponicidin's antitumor activity against HCC.
  • Ponicidin represents a promising therapeutic candidate for hepatocellular carcinoma treatment.
Keywords:
Hepatocellular carcinomaKeap1PGAM5apoptosismitochondrial functionponicidin

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