Potential of β-elemene induced ferroptosis through Pole2-mediated p53 and PI3K/AKT signaling in lung cancer cells

Ferroptosis is crucial for tumor growth inhibition. Moreover, ferroptosis has been considered as a potential strategy against cancer. The present study focused on the mechanism of ferroptosis induction by β‐elemene during the lung cancer (extracted from the Chinese medicine Curcuma Wen yujin). CCK-8 assay, flow cytometry and biochemical assays including intracellular ROS, MDA, GSH, iron and 8-OHdG level were performed. DNA polymerase epsilon subunit 2 (Pole2) and the ferroptosis-related proteins were studied by utilizing western blotting. The study results showed that the β‐elemene reduced the viability of lung cancer cells via ferroptosis. Furthermore, multiple experiments confirmed that Pole2 knockdown enhanced the production of lipid ROS, MDA and iron, leading to the iron-dependent ferroptosis in lung cancer cells. Overexpression of Pole2 inhibited β‐elemene-induced ferroptosis through reduction of iron-dependent oxidative damage. Mechanically, Pole2 reduced the upregulation of p53 expression, and increased the phosphorylation levels of PI3K and AKT in β‐elemene-induced cells. Overexpression of TP53 or the inhibitor of PI3K/AKT pathway reversed the effects of Pole2. Together, β‐elemene evoked ferroptosis through the Pole2-regulated p53 or PI3K/AKT signalling, and might be an effective therapy for lung carcinogenesis.