Sevoflurane suppresses growth and metastasis of bladder cancer cells via inducing ferroptosis and antitumor microenvironment through Akt/mTOR/SREBP1 signaling.

Abstract

Sevoflurane is a volatile anesthetic commonly used in clinics, and whether prolonged and repeated exposure to sevoflurane has a potential influence on bladder cancer progression is uncertain. Cell viability assays, transwell assays, flow cytometry, animal models, immunohistochemistry (IHC) staining, western blotting, and reverse transcription-quantitative PCR (RT-qPCR) were performed to evaluate the potential influence of sevoflurane on bladder cancer cells. Multiple rounds of sevoflurane treatment inhibited growth and metastasis and promoted reactive oxidative species (ROS) generation and ferroptosis in bladder cancer cells. In immunocompetent mice, repeated sevoflurane exposure induces an antitumor immune response in bladder cancer xenografts in vivo, whereas inhibition of ferroptosis abrogates this effect. Mechanistically, multiple rounds of sevoflurane exposure modulated lipid oxidation and lipogenesis in bladder cancer cells via the inhibition of Akt/mTOR/SREBP1 signaling, and reactivation of this signaling abrogated the influence of sevoflurane on ferroptosis and bladder cancer progression. Our results indicate that long-term and repeated exposure to sevoflurane suppresses the growth and metastasis of bladder cancer cells by inducing ferroptosis and the antitumor microenvironment by suppressing Akt/mTOR/SREBP1 signaling. Our data suggest a novel role of sevoflurane in bladder cancer progression and treatment.