Etomidate Induces Mitochondrial Dysfunction in Glioma Cancer Cells by Inhibiting Mitochondrial Biogenesis Mediated by
Hailiang Shi1, Zhongcheng Cao2, Kai Wei3
1Department of Neurosurgery, The First People's Hospital of Jiangxia District, Wuhan City, Wuhan, Hubei, China.
Abstract:
Gliomas are one of the most prevalent types of solid tumors in the brain. Imbalances in mitochondrial metabolism have been implicated in the pathological progression of gliomas. Etomidate, an agonist of the γ-aminobutyric acid type A (GABAA) receptor, is widely used in clinical settings. In this study, we report a novel pharmacological function of etomidate in regulating mitochondrial metabolism in glioma cancer cells. U87 glioma tumor cells were treated with etomidate (0.5, 1.0, and 2.0 µg/mL) for 24 h. Quantitative real-time PCR, western blot analysis, mtDNA/nDNA ratio, MitoTracker Red staining, Complex I and IV activity, intracellular ATP levels, and mitochondrial respiration were assessed. First, etomidate exposure inhibited the expression of PGC-1α in U87 glioma tumor cells. Further investigation revealed that etomidate suppressed the expression of Nrf1 and TFAM, the two key executors of mitochondrial biogenesis. Etomidate treatment led to damage in mitochondrial biogenesis by decreasing the mtDNA/nDNA ratio, reducing the protein expression of cytochrome B, and lowering mitochondrial mass. These changes suggest impaired mitochondrial replication and function. Correspondingly, etomidate exposure induced a "loss of mitochondrial function" by diminishing the activities of Complex I and Complex IV, the mitochondrial respiratory rate (MRR), and ATP generation. These effects highlight the detrimental impact of etomidate on the energy metabolism of glioma cells. Mechanistically, etomidate inactivated the transcription factor CREB by reducing its phosphorylation at Ser133. Activation of CREB with the second messenger cAMP restored the expression of PGC-1α, the mtDNA/nDNA ratio, Complex IV activity, summarized mitochondrial respiratory rate (MRR), and ATP production. This suggests that CREB activation may serve as a potential therapeutic strategy to counteract etomidate's inhibitory effects on mitochondrial function in glioma cells. Our results suggest that damage to mitochondrial biogenesis is a key step in the anticancer properties of etomidate in gliomas, and the decrease in PGC-1α and its downstream molecules may be the critical mechanism behind this effect.
Insights
Etomidate damages glioma cell mitochondrial function by inhibiting PGC-1α and CREB, impacting cancer cell energy. Restoring CREB activity may counteract these effects, suggesting a novel anticancer mechanism.
Area of Science:
- Molecular Biology
- Cancer Research
- Mitochondrial Biology
Background:
- Gliomas are common brain tumors where mitochondrial metabolism is crucial for progression.
- Etomidate, an anesthetic, is explored for novel roles beyond its GABAergic effects.
- Mitochondrial dysfunction is increasingly recognized in cancer pathology.
Purpose of the Study:
- To investigate the novel pharmacological function of etomidate on mitochondrial metabolism in glioma cells.
- To elucidate the molecular mechanisms by which etomidate affects glioma cell energy production.
- To explore potential therapeutic strategies targeting etomidate's effects on glioma mitochondria.
Main Methods:
- U87 glioma cells treated with etomidate.
- Assessed gene/protein expression (PGC-1α, Nrf1, TFAM, CREB), mtDNA/nDNA ratio, mitochondrial mass, and Complex I/IV activity.
- Measured intracellular ATP levels and mitochondrial respiration rate (MRR); cAMP used to activate CREB.
Main Results:
- Etomidate inhibited PGC-1α, Nrf1, and TFAM, impairing mitochondrial biogenesis and reducing mtDNA/nDNA ratio and mitochondrial mass.
- Etomidate decreased Complex I/IV activity, MRR, and ATP levels, indicating impaired mitochondrial function and energy metabolism.
- Etomidate inactivated CREB; cAMP-mediated CREB activation restored mitochondrial function and ATP production.
Conclusions:
- Etomidate damages glioma cell mitochondrial biogenesis and function, contributing to its anticancer properties.
- Inhibition of PGC-1α and downstream molecules via CREB inactivation is a key mechanism of etomidate's effect.
- CREB activation presents a potential therapeutic strategy to reverse etomidate-induced mitochondrial dysfunction in gliomas.
