A Novel PPARγ Modulator Falcarindiol Mediates ER Stress-Mediated Apoptosis by Regulating NOX4 and Overcomes Radioresistance in Breast Cancer

The extract of the rhizome of Cnidium officinale Makino has potential anti-cancer and anti-inflammatory effects in many diseases, such as cancer. However, the biological functions of falcarindiol (FAD) in breast cancer are not fully understood. This study proved the anti-inflammatory and anti-cancer effects of FAD in breast cancer. Breast cancer models confirmed that FAD reduces cell viability and decreases the tumor volume of xenograft mouse models in a dose-dependent manner. FAD mediated caspase-3-dependent apoptosis in MDA-MB-231 and MCF-7 cells, whereas Z-VAD-FMK in combination with FAD inhibited caspase-3-induced apoptosis. FAD mediates apoptosis through cytosolic reactive oxygen species (ROS) and calcium (Ca²⁺) production and ER stress signaling pathways. In addition, FAD combined with thapsigargin (TG) exerts a synergistic apoptotic cell death effect. In the loss-of-function experiments, PERK or CHOP ablation suppressed intracellular ROS and Ca²⁺ release and ER stress-induced apoptosis in FAD-treated breast cancer models. Since there is a relationship between ROS and NADPH Oxidase 4 (NOX4), Nox4 ablation blocked ER stress-mediated apoptotic cell death by inhibiting ROS release in FAD-induced breast cancer models. Radioresistant models, such as MCF-7R and MDA-MB-231R, were developed to address the cellular radioresistance in clinical radiotherapy. FAD combined with radiation (2 Gy) overcame radioresistance via the inhibition of the epithelial-mesenchymal transition (EMT) phenomenon, such as the upregulation of PPARγ, VIM, and CDH2 and the downregulation of CDH1. Consequently, these results show that FAD may be a novel treatment as a breast cancer therapy.