Oridonin interrupts cellular bioenergetics to suppress glioma cell growth by down-regulating PCK2

Jianhu Lin1, Shanshan Wu1, Sisi Ye1

  • 1Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

Insights

Oridonin, a natural compound, effectively inhibits glioma growth by targeting PCK2. This mechanism disrupts cellular energy production and increases oxidative stress, offering a new therapeutic strategy for glioma.

Area of Science:

  • Oncology
  • Biochemistry
  • Pharmacology

Background:

  • Glioblastoma is an aggressive brain tumor with limited treatment options.
  • Tumor metabolism plays a critical role in glioblastoma progression.
  • Oridonin, derived from Rabdosia rubescens, shows potential anti-cancer properties.

Purpose of the Study:

  • To evaluate the anti-tumor effects of Oridonin on glioma cells.
  • To elucidate the mechanism of Oridonin's action, focusing on tumor metabolic suppressive activity.
  • To investigate the role of PCK2 (phosphoenolpyruvate carboxykinase 2) in Oridonin's anti-glioma effects.

Main Methods:

  • In vitro assays (CCK8, RTCA, colony formation, flow cytometry, wound healing, Transwell) and in vivo xenograft models were used to assess Oridonin's efficacy.
  • Cellular bioenergetics were measured using Seahorse analysis.
  • RNA-sequencing and bioinformatics analysis of TCGA/CGGA data were employed to identify molecular targets, specifically PCK2, which was further validated by gene knockdown experiments.

Main Results:

  • Oridonin significantly inhibited glioma cell growth both in vitro and in vivo.
  • Oridonin treatment reduced cellular oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), indicating metabolic suppression.
  • Oridonin down-regulated PCK2 expression, and PCK2 depletion mimicked Oridonin's effects on cell growth and bioenergetics.
  • PCK2 was found to be upregulated in high-grade gliomas and associated with poor patient outcomes.

Conclusions:

  • Oridonin exhibits potent anti-tumor properties against glioma.
  • Oridonin exerts its effects by inducing an energy crisis and increasing oxidative stress in glioma cells.
  • PCK2 is identified as a novel molecular target of Oridonin in glioma therapy.

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