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CircZFR involves propofol-triggered ferroptosis in lung cancer cells through the IGF2BP2/GPX4 axis
Xiaocui Yu1, Yuhui Gu2, Shao Wang3
1Department of Anesthesiology, The First Affiliated Hospital of Shaoyang University, Shaoyang, P. R. China.
Abstract:
This study aims to delineate the underlying mechanism by which propofol triggers ferroptosis in lung cancer cells through the inhibition of the circZFR/IGF2BP2/GPX4 axis. The expression levels of circZFR, insulin-like growth factor 2 binding protein 2 (IGF2BP2), and glutathione peroxidase 4 (GPX4) in lung cancer cells were assessed using quantitative real-time polymerase chain reaction and Western blot analysis. Cell viability was evaluated with the cell counting kit-8 assay, and ferroptosis-related indicators were measured using appropriate kits. The interactions between circZFR and IGF2BP2, as well as between GPX4 and IGF2BP2, were investigated through RNA pull-down and RNA immunoprecipitation assays, and their effects on ferroptosis were analyzed using rescue assays. In addition, xenograft assays in nude mice were conducted to evaluate the impact of propofol on tumor growth and ferroptosis in vivo. Propofol treatment induced cell ferroptosis, as evidenced by decreased cell viability and elevated levels of malondialdehyde (MDA), Fe2+, and lipid reactive oxygen species in H1299 and SPC-A-1 cells. In addition, propofol reduced the expression of circZFR and GPX4 in lung cancer cells. Notably, the overexpression of circZFR inhibited propofol-induced ferroptosis in these cells. CircZFR interacts with IGF2BP2 to regulate the stability of GPX4 mRNA and its protein expression. Furthermore, circZFR inhibited GPX4-mediated ferroptosis by enhancing IGF2BP2 expression in both H1299 and SPC-A-1 cell lines. Moreover, propofol inhibited tumor growth in nude mice, downregulated the expression of circZFR, IGF2BP2, and GPX4, and increased MDA and Fe2+ levels in tumor tissues. Propofol downregulates circZFR to inhibit the expression of GPX4 by interacting with IGF2BP2, thereby triggering ferroptosis in lung cancer cells.
Insights
Propofol triggers ferroptosis in lung cancer by downregulating circZFR, which stabilizes GPX4 mRNA via IGF2BP2. This mechanism inhibits tumor growth and offers a potential therapeutic strategy for lung cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Lung cancer remains a leading cause of cancer-related mortality worldwide.
- Understanding the molecular mechanisms of cancer cell death, such as ferroptosis, is crucial for developing novel therapeutic strategies.
- Propofol, a common anesthetic, has shown potential anti-cancer effects that warrant further investigation.
Purpose of the Study:
- To elucidate the mechanism by which propofol induces ferroptosis in lung cancer cells.
- To investigate the role of the circZFR/IGF2BP2/GPX4 axis in propofol-mediated ferroptosis.
- To evaluate the therapeutic potential of propofol in preclinical lung cancer models.
Main Methods:
- Quantitative real-time PCR and Western blot analysis to assess gene and protein expression.
- Cell counting kit-8 assay and ferroptosis indicator kits to measure cell viability and ferroptosis.
- RNA pull-down and RNA immunoprecipitation assays to investigate molecular interactions.
- Rescue assays and xenograft tumor models in nude mice to validate findings in vitro and in vivo.
Main Results:
- Propofol induced ferroptosis in lung cancer cells (H1299 and SPC-A-1), indicated by reduced viability and increased MDA, Fe2+, and lipid ROS.
- Propofol downregulated circZFR and GPX4 expression, while circZFR overexpression attenuated propofol-induced ferroptosis.
- CircZFR interacts with IGF2BP2 to regulate GPX4 mRNA stability and protein expression, inhibiting ferroptosis.
- In vivo, propofol inhibited tumor growth, downregulated circZFR, IGF2BP2, and GPX4, and increased ferroptosis markers.
Conclusions:
- Propofol triggers ferroptosis in lung cancer cells by downregulating circZFR, which subsequently inhibits GPX4 expression via IGF2BP2.
- The circZFR/IGF2BP2/GPX4 axis is a key mediator of propofol's anti-cancer effects.
- Propofol demonstrates therapeutic potential against lung cancer by inducing ferroptosis, suggesting its utility as an anti-cancer agent.
