The mechanism of sevoflurane affecting ovarian cancer cell proliferation and migration by regulating RNA methylase TRDMT1 to activate the β-catenin pathway

Objective: Sevoflurane (Sevo), a commonly used inhalant anesthetic clinically, is associated with a worsened Cancer prognosis, and we investigated its effect on RNA methylase tRNA aspartic acid methyltransferase 1 (TRDMT1) expression and ovarian Cancer (OC) cell malignant phenotypes.

Methods: Human OC cells (OVCAR3/SKOV3) were pretreated with 3.6% Sevo and cultured under normal conditions for 48 h, with their viability assessed. After 2-h Sevo treatment or interference plasmid transfections to down-regulate TRDMT1/adenomatous polyposis coli (APC), changes in TRDMT1, APC and β-catenin expression, cell proliferative activity, cycle, Apoptosis, migration, invasion, and 5-methylcytosine (m5C) methylation potential modification sites were evaluated. Additionally, APC mRNA m5C methylation level and stability, the binding of APC mRNA with TRDMT1, the binding intensity of APC and β-catenin, and β-catenin nuclear translocation were detected Lastly, Cyclin D1, cellular-myelocytomatosis viral oncogene (c-Myc) and β-catenin protein levels, and ki67-positive rate were assessed.

Results: Sevo treatment boosted cell cycle, proliferation, migration and invasion, suppressed Apoptosis and APC expression, and up-regulated c-Myc, β-catenin, TRDMT1 and Cyclin D1 levels. Silencing TRDMT1 or β-catenin partially averted Sevo-mediated promotion effects on cell malignant biological behaviors. Lowly-expressed APC annulled the effect of silencing TRDMT1 and promoted cell malignant behaviors. Sevo enhanced APC mRNA m5C modification and degradation and activated the APC/β-catenin pathway by increasing TRDMT1, thus encouraging OC growth in vivo.

Conclusions: Sevo stimulated APC m5C modification and curbed its expression by up-regulating TRDMT1, which in turn activated the β-catenin pathway to stimulate OC cell cycle, invasion, proliferation, and migration and to suppress Apoptosis.

5-methylcytosine; Adenomatous polyposis coli; Cellular-myelocytomatosis viral oncogene; Cyclin D1; Ovarian cancer; Sevoflurane; TRNA aspartic acid methyltransferase 1; β-catenin.