Maackiain induces apoptosis and autophagy via ROS-mediated endoplasmic reticulum stress in endometrial cancer

Abstract

Endometrial cancer (EC) is a common gynecological cancer, characterized by increasing incidence and mortality rates. Maackiain (MA), a natural flavonoid compound, has multiple biological activities, but little is known about how it affects EC cells. In the present study, CCK-8, EdU, colony formation, and flow cytometry assays were used to evaluate the effects of MA on EC cell proliferation, apoptosis, and reactive oxygen species (ROS) levels. The effect of MA on autophagy in EC cells were examined through the observation of cell morphology and ultrastructure, and cells were transfected with AdPlus-mCherry-GFP-LC3B for further analysis. Transcriptomic and western blot analyses revealed the underlying mechanism. To evaluate the anti-EC effect of MA in vivo, a xenograft model was established. The results demonstrated that MA inhibited KLE and Ishikawa cell growth in a dose-dependent manner. Furthermore, MA significantly suppressed EC xenograft tumor growth in vivo while exhibiting low toxicity. In addition, EC cells treated with MA exhibited pro-apoptotic and pro-autophagic responses, with the latter exhibiting cytoprotective properties. MA also induced the accumulation of ROS, which promoted endoplasmic reticulum (ER) stress. Notably, the use of the N-acetyl-L-cysteine (NAC) ROS scavenger and the 4-phenylbutyric acid (4-PBA) ER stress inhibitor effectively mitigated the autophagy and apoptosis induced by MA. These results collectively implied that MA triggers autophagy and apoptosis in EC cells through ROS-mediated ER stress, highlighting its potential as a therapeutic agent against EC.