Dataset Information

Propofol enhances stem-like properties of glioma via GABA_AR-dependent Src modulation of ZDHHC5-EZH2 palmitoylation mechanism.

ABSTRACT:

Background

Propofol is a commonly used anesthetic. However, its effects on glioma growth and recurrence remain largely unknown.

Methods

The effect of propofol on glioma growth was demonstrated by a series of in vitro and in vivo experiments (spheroidal formation assay, western blotting, and xenograft model). The acyl-biotin exchange method and liquid chromatography-mass spectrometry assays identified palmitoylation proteins mediated by the domain containing the Asp-His-His-Cys family. Western blotting, co-immunoprecipitation, quantitative real-time polymerase chain reaction, co-immunoprecipitation, chromatin immunoprecipitation, and luciferase reporter assays were used to explore the mechanisms of the γ-aminobutyric acid receptor (GABA_AR)/Src/ZDHHC5/EZH2 signaling axis in the effects of propofol on glioma stem cells (GSCs).

Results

We found that treatment with a standard dose of propofol promoted glioma growth in nude mice compared with control or low-dose propofol. Propofol-treated GSCs also led to larger tumor growth in nude mice than did vector-treated tumors. Mechanistically, propofol enhances the stem-like properties of gliomas through GABA_AR to increase Src expression, thereby enhancing the palmitoylation of ZDHHC5-mediated EZH2 and Oct4 expression.

Conclusion

These results demonstrate that propofol may promote glioma growth through the GABA_AR-Src-ZDHHC5-EZH2 mechanism and are helpful in guiding the clinical use of propofol to obtain a better patient prognosis after the surgical resection of tumors.

SUBMITTER: Fan X

PROVIDER: S-EPMC9351178 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Publications

Propofol enhances stem-like properties of glioma via GABA<sub>A</sub>R-dependent Src modulation of ZDHHC5-EZH2 palmitoylation mechanism.

Fan Xiaoqing X Gong Meiting M Yu Huihan H Yang Haoran H Wang Sheng S Wang Ruiting R

Stem cell research & therapy 20220804 1

<h4>Background</h4>Propofol is a commonly used anesthetic. However, its effects on glioma growth and recurrence remain largely unknown.<h4>Methods</h4>The effect of propofol on glioma growth was demonstrated by a series of in vitro and in vivo experiments (spheroidal formation assay, western blotting, and xenograft model). The acyl-biotin exchange method and liquid chromatography-mass spectrometry assays identified palmitoylation proteins mediated by the domain containing the Asp-His-His-Cys fam ...[more]

PMID: 35927718

Similar Datasets

Project description:Although propofol is among the most commonly administered general anesthetics, its mechanism of action is not fully understood. It has been hypothesized that propofol acts via a similar mechanism as (R)-ethyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate (etomidate) by binding within the GABAA receptor transmembrane receptor domain at the two β +/α - subunit interfaces with resultant positive allosteric modulation. To test this hypothesis, we leveraged the ability of diazepam to bind to those sites and act as a competitive antagonist. We used oocyte-expressed α 1 β 3 γ 2L GABAA receptors to define the actions of diazepam (± flumazenil) on currents activated or potentiated by propofol and a zebrafish activity assay to define the impact of diazepam and flumazenil on propofol-induced anesthesia. We found that diazepam increased the amplitudes of GABAA receptor-mediated currents at nanomolar concentrations but reduced them at micromolar concentrations. The current amplitude changes produced by nanomolar diazepam concentrations were inhibited by flumazenil whereas those produced by micromolar diazepam concentrations were not. Studies of agonist potentiation showed that the micromolar inhibitory action of diazepam was surmountable by high concentrations of propofol and produced a rightward shift in the propofol concentration-response curve characterized by a Schild slope not statistically significantly different from 1, consistent with competition between diazepam and propofol. Although micromolar concentrations of diazepam (plus flumazenil) similarly reduced GABAA receptor currents modulated by propofol and etomidate, it only reduced the anesthetic actions of etomidate. We conclude that while both propofol and etomidate can modulate GABAA receptors by binding to the β +/α - subunit interfacial sites, propofol-induced anesthesia likely involves additional target sites. SIGNIFICANCE STATEMENT: Although the drug combination of diazepam and flumazenil reverses the GABAA receptor positive modulatory actions of both propofol and (R)-ethyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate (etomidate), it only reverses the in vivo anesthetic actions of etomidate. These results strongly suggest that distinct mechanisms of action account for the anesthetic actions of these two commonly administered anesthetic agents.

Dataset Information

Propofol enhances stem-like properties of glioma via GABA_AR-dependent Src modulation of ZDHHC5-EZH2 palmitoylation mechanism.

Background

Methods

Results

Conclusion

Publications

Propofol enhances stem-like properties of glioma via GABA<sub>A</sub>R-dependent Src modulation of ZDHHC5-EZH2 palmitoylation mechanism.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Propofol enhances stem-like properties of glioma via GABAAR-dependent Src modulation of ZDHHC5-EZH2 palmitoylation mechanism.

Background

Methods

Results

Conclusion

Publications

Propofol enhances stem-like properties of glioma via GABA<sub>A</sub>R-dependent Src modulation of ZDHHC5-EZH2 palmitoylation mechanism.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Propofol enhances stem-like properties of glioma via GABA_AR-dependent Src modulation of ZDHHC5-EZH2 palmitoylation mechanism.