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

Abstract

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.

Keywords

• falcarindiol
• Nox4
• ER stress
• cell death
• ROS