Amentoflavone attenuates cell proliferation and induces ferroptosis in human gastric cancer by miR‐496/ATF2 axis

Abstract

Amentoflavone (AF) is a natural multifunctional biflavonoid that has been revealed to possess multiple biological activities, including anticancer activity. Here, this work focused on exploring the functions and mechanism of AF in gastric cancer (GC). Levels of genes and proteins were examined by quantitative real‐time PCR and western blotting. Cell proliferation and cell death were analyzed using cell counting kit‐8, colony formation, and lactate dehydrogenase (LDH) release assay, respectively. Cell ferroptosis was evaluated by detecting the levels of malondialdehyde (MDA), reduced glutathione (GSH), Fe2+, and intracellular reactive oxygen species (ROS). The binding between miR‐496 and activating transcription factor 2 (ATF2) was confirmed by using dual‐luciferase reporter assay. Murine xenograft assay was conducted for in vivo experiments. The results showed that AF suppressed the proliferation and induced ferroptotic cell death in GC cells. MiR‐496 expression was decreased in GC tissues and cells, and AF treatment increased miR‐496 expression level in GC cells. Functionally, miR‐496 inhibition reversed the inhibitory effects of AF on GC cell proliferation and promoting effects on ferroptotic cell death. Mechanistically, ATF2 was targeted by miR‐496. ATF2 expression was increased in GC tissues and cells, which was decreased by AF treatment and subsequently rescued by miR‐496 downregulation in GC cells. Moreover, miR‐496 overexpression suppressed the proliferation and induced ferroptotic cell death in GC cells via targeting ATF2. In all, AF suppressed the proliferation and induced ferroptotic cell death in GC cells via miR‐496/ATF2 axis, indicating a novel therapeutic approach for GC patients.

Induction of ferroptosis by natural phenols: A promising strategy for cancer therapy

“…AMF has been shown to cause ferroptotic death in gastric cancer via downregulating a transcription factor named ATF2 and decreasing its target genes, including GPX4 and SLC7A11. Thus, AMF could alter the metabolism of lipids, amino acids, and iron by affecting ACSL4, GSH levels, and Fe 2+ levels in cancer cells (Tang et al, 2023). In glioma cell lines, the activation of the AMPK/mTOR pathway by AF triggers autophagy and diminishes FTH levels, and releasing Fe 2+ ions and Lipid ROS causes ferroptosis in vivo (Chen, Li, et al, 2020).…”