Gingerenone A attenuates gastric cancer progression via PI3K/Akt/FOXO1 signaling pathway, autophagy, and apoptosis

Abstract

Objective: To investigate anti-gastric cancer effects of gingerenone A (GA) and explore its association with the PI3K/Akt/FOXO1 signaling pathway, autophagy, and apoptosis.
Methods: Cell viabilities were detected via CCK-8 assay. Proliferation, migration, invasion, and apoptosis were assessed by colony formation, EdU, Transwell assays, and flow cytometry. Autophagy, mitochondrial dysfunction, and apoptosis were detected via Western blot, immunofluorescence, and staining assays. Inhibitors and siFOXO1 were used for molecular mechanism studies. An MKN-45 xenograft model was used to evaluate in vivo efficacy and safety.
Results: GA reduced gastric cancer cell proliferation, migration, and invasion, and promoted apoptosis, with MKN-45 cells being most sensitive. GA induced autophagy-related changes, mitochondrial dysfunction, and apoptosis-related changes, with suppression of PI3K/Akt signaling and reduced inhibitory phosphorylation of FOXO1; these effects were attenuated by the pharmacological and genetic interventions. In vivo, GA inhibited tumor growth without notable histopathological damage to major organs at the tested doses.
Conclusions: GA may exert anti-gastric cancer effects via PI3K/Akt/FOXO1 signaling pathway, with autophagy-related changes and apoptosis-related responses. It could be a candidate compound for gastric cancer therapy.

Keywords

Gingerenone A / Gastric cancer / PI3K/Akt/FOXO1 axis / Autophagy / Mitochondria-associated apoptosis / Diarylheptanoids / Oxidative stress / DNA damage

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