Dataset Information

Anesthetic Propofol Promotes Tumor Metastasis in Lungs via GABA_A R-Dependent TRIM21 Modulation of Src Expression.

ABSTRACT: Generation of circulating tumor cells (CTCs), a key step in tumor metastasis, occurs during surgical tumor resection, often performed under general anesthesia. Propofol is the commonly used anesthetic, but its effects on CTCs and tumor metastasis remain largely unknown. Propofol effects are investigated in an experimental metastasis model by injecting tumor cells and, subsequently, low- or standard-dose propofol to nude mice through tail vein. Propofol- or vehicle-treated tumor cells are also injected to the mice. An in vitro tumor cell-vascular endothelial cell adhesion assay, immunofluorescence, and other methods are employed to assess how propofol affects tumor cell adhesion and extension. Propofol induces more lung tumor metastasis in mice than control. Mechanistically, propofol enhances tumor cell adhesion and extension through GABA_A R to downregulate TRIM21 expression, leading to upregulation of Src, a protein associated with cell adhesion. These results demonstrate that propofol may promote tumor metastasis through GABA_A R-TRIM21-Src mechanism.

SUBMITTER: Liu Q

PROVIDER: S-EPMC8456212 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Anesthetic Propofol Promotes Tumor Metastasis in Lungs via GABA<sub>A</sub> R-Dependent TRIM21 Modulation of Src Expression.

Liu Qidong Q Sheng Zhihao Z Cheng Chun C Zheng Hui H Lanuti Michael M Liu Rong R Wang Ping P Shen Yuan Y Xie Zhongcong Z

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20210715 18

Generation of circulating tumor cells (CTCs), a key step in tumor metastasis, occurs during surgical tumor resection, often performed under general anesthesia. Propofol is the commonly used anesthetic, but its effects on CTCs and tumor metastasis remain largely unknown. Propofol effects are investigated in an experimental metastasis model by injecting tumor cells and, subsequently, low- or standard-dose propofol to nude mice through tail vein. Propofol- or vehicle-treated tumor cells are also in ...[more]

PMID: 34263559

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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

Anesthetic Propofol Promotes Tumor Metastasis in Lungs via GABA_A R-Dependent TRIM21 Modulation of Src Expression.

Publications

Anesthetic Propofol Promotes Tumor Metastasis in Lungs via GABA<sub>A</sub> R-Dependent TRIM21 Modulation of Src Expression.

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Dataset Information

Anesthetic Propofol Promotes Tumor Metastasis in Lungs via GABAA R-Dependent TRIM21 Modulation of Src Expression.

Publications

Anesthetic Propofol Promotes Tumor Metastasis in Lungs via GABA<sub>A</sub> R-Dependent TRIM21 Modulation of Src Expression.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Anesthetic Propofol Promotes Tumor Metastasis in Lungs via GABA_A R-Dependent TRIM21 Modulation of Src Expression.