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.
Abstract:
We aim to evaluate the tumor metabolic suppressive activity of Oridonin (extract of Rabdosia rubescens) in glioma and elucidate its potential mechanism. Effects of Oridonin on U251/U87 cells were determined by CCK8, RTCA, colony formation, flow cytometry, wound healing, and Transwell assay. Xenograft tumor model to evaluate the effect of Oridonin on glioma cells in vivo. Cellular bioenergetics were measured by Seahorse. RNA-seq was performed to screen potential biological pathways in Oridonin treated cells. Bioinformatics analysis of PCK2 in glioma was performed based on TCGA/CGGA. Endogenous PCK2 was knocked-down by lentivirus packaged shRNA. We found Oridonin significantly inhibited cell growth in U251/U87 in vitro and in vivo. Both oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were decreased in Oridonin-treated U251/U87 cells. Oridonin treatment led to PCK2 down-regulation. Additionally, PCK2 was up-regulated in higher grade glioma and correlated with poor outcomes. Furthermore, PCK2 depletion significantly inhibited cell growth and decreased OCR/ECAR in U251/U87 which coincided with the effects of Oridonin. Therefore, we evaluated the potent anti-tumor property of Oridonin in glioma. Importantly, we demonstrated that PCK2 might be a novel target of Oridonin on glioma by inducing energy crisis and increasing oxidative stress.
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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